Guidelines Cryptococcal Meningitis

7/30/2019 Guidelines Cryptococcal Meningitis

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T HE S OU TH ER N A FR IC AN J OU RN AL O F H IV M ED IC IN E S PR IN G 2 00 7 25

INTRODUCTION AND BACKGROUND

While the developed world has seen a substantial decl ine in

incidence rates of CC after the advent of highly active

antiretroviral treatment (HAART),1- 3 the enormi ty o f the

burden of AIDS on the Afr ican sub-cont inent and theanticipated delays in achieving ful l coverage of antiretroviral

therapy (ART) programmes imply that CC wil l continue to

cause mortal i ty among our population for years to come. The

prognosis of patients with cryptococcal meningitis was very

poor prior to the avai labi l i ty of ART,4- 6 but present survival

rates in the context of ART co-administration are much

improved.7- 9 Consequently it has become essential to

improve the initial acute management of CC in order to

maximise the patients chances of initial survival and

subsequent entry into the ART treatment programme.

Existing international guidel ines for the management of

cryptococcosis10-14 are written for different geographical andcl in ica l cont exts and may be imp ract icable for

imp lementa t i on i n sub-Saharan Af r i ca g i ven l im i ted

availabi l i ty of drugs and ot her resources.

OBJECTIVE A ND TARGET AUDIENCE OF GUIDELINES

The objective of these guidelines is:

To set best practice standards for prevention, diagnosis,

management and treatment of HIV-associated CC.

To provide practical guidance for doctors working without

special ist support who encounter CC in their routine

practice.

To identi fy gaps in the evidence base to guide furtherresearch.

G U I D E L I N E S

G u i d e l i n e s f o r t h e Pr e v e n t i o n ,

D i a g n o s i s a n d M a n a g e m e n t o f

C r y p t o c o c c a l M e n i n g i t i s a n dD i s s e m i n a t e d C r y p t o c o c c o s i s i n

H IV-i n f e c t e d pa t i e n t s

Convenors:

Ker r ig an M cCa rt h y Rep r od u ct i ve H ea lt h an d HI V Resea rc hUni t, Universi ty of t he Witw atersrand

Gr aem e M ei nt jes D iv isi on o f In f ect io us D isea ses an d HIVMedicine, University of Cape Town and

G F Jooste HospitalM embers of w rit ing committee:

Beth Arth ingt on- Skaggs M ycotic Diseases Branch, Centers forDisease Contro l, Atlant a, USA

Ti han a Bican ic St Geo rg es H osp it al M ed ical Sch oo l,London

M ark Cot ton Depar t men t of Paediat rics, St el len -bosch University

Tom Chil ler Epidem iology Unit , M ycotic DiseasesBranch, Centers for Disease Control,Atlanta, USA

Nelesh Govender M ycology Reference Uni t , Natio nalInst i tute for Commun icable Diseases

To m Harr ison Dep ar tm en t of In fect io us Diseases, StGeorges Hospi tal Medical School ,

LondonAlan Kar st aed t Dep ar tm en t of M edicin e, Un iversit y of

the Witwatersrand

Gary M aart en s Division o f Cl in ical Ph ar macolog y,Department of Medic ine, Universi ty ofCape Town

Ebr ah im Varavia Dep ar tm en t o f M e di cin e, Tsh ep on gHospi tal , North W est Province

Fr an co is Ven ter Rep ro du ct iv e H ealt h an d HIV Resear chUni t, Universi ty of t he Witw atersrand

Hest er Vism er PROM EC Un it , M edical Resear chCouncil, Tygerberg

Internat ional reviewers:David Lalloo Liverpool School o f Trop ical M edi-

cine, UK

Robert A Larson Depar t m en t o f M ed icine, Un i-versity of Southern California, USA

So m n u ek Su n g ka nu p ar p h M a h i d ol U n i ve rsi t y, B an g k ok ,Thailand

Acknowlegements:Brian Eley and Helena Rabie for comments on management ofpaediatric cryptococcosis.

A note on definitions:Cryptococcal meningi t is (CM) refers to meningo-encephal i t is

resul t ing from infect ion; disseminated cryptococcosis refers to

infection of multiple body sites; and cryptococcosis (CC) refers to

infect ion of any body s i te, wi th an organism from the genus

Cryptococcus, inc luding Cryptococcus neoformans an d C. gatti i

( fo rmer l y C. neoformans var. ga t t i i ) . Where the term

cryptococcosis (CC) is used in this document, it refers to either

cryptococcal meningi t is or disseminated cryptococcosis.

Pfizer supported the cost of theguideline writing committee andthe poster supplied as an insert

to this issue of the journal.


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S PR IN G 2 00 7 T HE S OU TH ER N A FR IC AN J OU RN AL O F H IV M ED IC IN E26

These guidel ines do not provide guidance for the m anagement

of CC in HIV-negative persons, or pulmonary cryptococcosis,

or cryptococcosis wit h l imited organ involvement . Crypto-

coccosis rarely occurs in HIV-un infected individu als and t here

are important d i f ferences in the management of these

patients. HIV-positive patients wit h apparently l imit ed organ

involvement due to C. neoformans (e.g. cutaneous crypto-

coccosis) almost always have disseminated disease.

STRUCTURE OF THE GUIDELINES

Part 1 compr ises guidel ines present ed as a stat ement in a

text box fol lowed by explanatory notes.

Part 2 ( to be found on the HIV Society websi te,

www.sahivsoc.org) presents a just i f icat ion of or

explanation for the gu idel ine, quot ing avai lable evidence.

PART 1: GUI DELIN ES W ITH EXPLAN TORY NOTES

W HEN TO CONSIDER THE DIAGNO SIS OF CC

Suspect cryptococcosis in a l l pat ients present ing wi th

meningi t is :

Cryptococcosis is a common cause of meningitis in the

AIDS era.

Patients m ay not be aware of th eir HIV status and m ay be

in a good state of health without features of HIV or AIDS

at time of presentation with CC.

Clinical presentation of patients with cryptococcosis may

include:

Symptoms and signs re lated to ra ised in tracrania l

pressure: headache, confusion, a l tered level of

consciousness, 6th cranial nerve palsies wit h d iplopia and

visual impairment , papi l loedema

Fever of unknown origin

Encephali tic symptoms including memory loss and new-onset psychiatric symptoms

Cutaneou s lesions (Fig. 1)

Pulmonary involvement including cavitation, infi l tration

and consolidation.

Patients with CM may not have neck sti ffness.

LUM BAR PUN CTURE AN D CT BRAIN

LP is essential in order to establish an aetiological diagnosis of

suspected m eningitis. LP may also al leviate sympto ms such as

headache, altered level of consciousness and 6th nerve palsies

wh ich are a result of raised int racranial pressure.

Focal neurological signs in CM are relatively uncommon;

wh ere avai lable, CT brain should be perfo rmed f irst in order to

exclude the presence of space-occupying lesions. In resource-

constrained settings where CT brain is not immediately

available or likely to be significantly delayed, LP may be donewithout prior CT brain.

At LP, in suspected CC:

M easure opening CSF pressure (nor m al


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Consider the f ol lowin g investigations: Adenine deaminase

(ADA), smear and culture for Mycobacterium tuberculosis

(requires at least 5 ml CSF), TPHA for syphi l i t ic menin gitis,

Toxoplasma gondii IgG and IgM.

Retain a tube of CSF at room temperature in event of

laboratory error.

I f insuff ic ient CSF is submi tted, the laboratory wi l l

priori tise tests to be performed.

Contact detai ls for procurement of CSF manometer sets

may be found in Appendix 2.

RECURRENT CC

A recurrent episode of CC is defined as:

1 . Re-appearance o f sympt oms o f cryp tococcosi s

(headaches, neck sti ffness and/or other neurological

man i fes ta t i on ) a f te r symptoms had fu l l y reso l ved

fo l lowing t reatm ent for the in i t ia l ep isode

WITH

2. Appropr iate laboratory conf i rmation of the d iagnosis

refer to recommendation 2 below.

In our context, recurrent CC may be a consequence of:

Inadequa te t rea tmen t o f the f i r s t ep i sode o f

cryptococcosis (through administration of fluconazole in

the in tensive phase, or insuff ic ient dose/durat ion of

fluconazole in the consolidation phase or fai lure to

manage raised int racranial pressure appropriately)

Failure to adhere to secondary prophylaxis (due to patient

or health care service provider factors)

In the context of ART, immune reconsti tution inflam-

mat ory syndrom e (IRIS)

Developm ent of microbiological resistance to flu conazole.

Patients with suspected recurrence of CC require a lumbar

puncture. Cl inicians should not assume that symptoms are

indicative of a recurrence. LP has the f ol lowin g advantages:

The LP identi fies the aetiological agent of meningitis and

wil l provide a diagnosis of other infections i f present.

The LP provides the laboratory wi th an iso late for

susceptibi l i ty t esting i f this is avai lable.

The LP establishes a diagnosis of raised intracranial

pressure, and f aci l i tates appropriate m anagement t hereof.

RECOM M ENDATION 2 : INITIAL TREATM ENT OFCRYPTOCOCCOSIS

1. Anti fungal t reatm ent of a f i rst episode of CC

Induct ion phase: Amphoter ic in B 1 mg/kg/dose

iv i for 2 weeks (min imum 1

week).

Consolidation phase: Fluconazole 400 mg po dai ly for8 weeks.

Secondary prophylaxis: Fluconazole 200 mg po dai ly for

l i fe or unt i l CD4 >200 cel ls/ l

for m ore than 6 mont hs on ART

(at least 12 m ont hs fluconazole

in t ota l ).

2. Antifungal treatment of a subsequent episode* of CC

tha t is though t to be due to flucon azole resistan ce:

Induct ion phase: Amphoter ic in B 1 mg/kg/dose

ivi for 2 - 4 weeks or unt i l CSF is

sterile.Consolidation phase: Fluconazole 800 mg po dai ly for

8 weeks wi th or wi t hout weekly

ampho ter i ci n B 1 mg/kg .

Secondary prophylaxis: Fluconazole 400 mg po dai ly for

l i fe (at least 12 months flu-

conazole in total)

OR

Weekly ampho te r ic in B 1 mg/

kg/dose

OR

week ly ampho ter i ci n B 1 mg/

kg/dose plus dai ly fluconazole

400 mg.

Secondary prophylaxis can be

discontinued i f CD4 count is

>200/ l for 6 mont hs on ART.

3. Management of raised intracranial pressure (>20 cm

CSF)

Alleviate pressure initial ly by draining not more than

20 - 30 ml of CSF ( to decrease opening pressure by 20 -

Fig. 2. Measurem ent of CSF openin g pressure usingmanometer.


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AN TIFUNGAL TREATM ENT OF A FIRST EPISODEOF CC

Infectious Diseases Society of America (IDSA) guidelines10 an d

other international guidel ines recommend induction phaset r ea tm en t w i t h 0 .7 - 1 m g /kg /do se a m p ho ter ic in B A N D

100 mg/kg/day 5- f lucytosine; unfor tun ate ly the lat t er drug is

not avai lable in sout hern Afr ica.

In head- to -head t r i a l s , the comb ina t i on 5 -FC w i th

amphoter ic in B 0.7 mg/kg/dose is super ior to amphoter ic in B

0.7 mg/kg/do se alone16 in terms of early fungicidal activi ty. In

th e absence of 5-f lucytosine, the writ ers bel ieve that sout hern

African patients should be treated with the higher dose of

ampho te r i c i n B 1 mg/kg /dose. In Sou th A f r i can adu lts

amphoter ic in B 1 mg/kg/dose is wel l to lerated.17

Amphotericin B in the induction phase should be given for 2

weeks; however, 7 - 10 days may suff ice.18

Where amph otericin B is un available or cannot be given safely,

transfer the patient to a centre where amphotericin B is

avai lable. If this is not possible, substi tute amphotericin B

induct ion phase treatm ent wi th f luconazole 800 mg po dai ly

for 4 weeks fo l lowed by f luconazole 400 mg dai ly for 8 weeks

(cont inuat ion phase). Amphoter ic in B is super ior to

fluconazole at lower fluconazole doses.17,19,20 There are no

studies comparing higher dose fluconazole with amphotericin

B, but given that fluconazole is fungistatic, amphotericin B

should always be the drug of fi rst choice.

Give fluconazole intravenously in patients who are vomitingor com atose and unable to take i t oral ly.

Refer for pal l iative care those patients who fai l to respond to

anti fungal therapy and management of raised intracranial

pressure, once other pathologies have been excluded.

AN TIFUNGAL TREATM ENT OF A SUBSEQUEN TEPISODE OF CC

Establ ish whether the patient was adherent to secondary

prophylaxis. If not adherent, address the reasons, and treat as

for the f irst episode of CC.

If the patient is on ART, this episode of CC may meet the

definit ion f or IRIS, in which case Recomm endation 5 shou ld be

fo l lowed.

M AN AGEM ENT OF RAISED IN TRACRANIAL PRESSURE

CSF opening pressure should be measured with every LP that

is performed (Fig. 2). Patients with raised intracranial pressure

exper ience considerable re l ie f o f symptoms fo l lowing

therapeutic LP.

Patients wi th persistent pressure symptoms that fa i l to

respond to serial lumbar punctures may require lumbar drain

insertion or shunting procedures. Neurosurgical consultation

should be sought.

Pat ients wi th CM should not be treated wi th adjunct ive

steroids as th is may adversely aff ect th e prognosis.

LABORATORY- BASED SURVEILLAN CE FOR CC

South Africa has an active survei l lance programme for CC.

(Refer to Appendix 3.)

RECOM M ENDATION 3 : ROLE OF THE LABORATORYIN THE DIAGN OSIS AND TREATM ENT OF CC

1. The laborato ry diagn osis of crypt ococcosis

A case of cryptococcosis may be diagnosed definitively

by culture or presumptively by tests indicating the

presence of Cryptococcusspecies, including a positive

India ink (Fig. 3) or cryptococcal antigen detection test

on any spec imen o r muc ica rmine-s ta ined h i s to -

patholog ical sections revealing th e organism.

2. The role of antifungal susceptibility testing (AFST) in

management of CC

AFST of C. neoformansagainst amphotericin B has no

ro le in pat ient m anagement.

AFST against fluconazole is not advised in first episodes

of CC, but may have value in recurrent or unresponsivecases where testing is available.

50%) at initial LP. Thereafter the need for pressure relief

should be dictated by recurrence of symp tom s of raised

intracranial pressure. Patients may require daily LPs.

4. Pain and symptom management

Reduction of intracranial pressure al leviates headache

and confusion. Residual pain may be managed with

paracetamol and mild opiates (WHO level 1 and 2

analgesics15 ) . Non-stero idal ant i - in f lammatory drugs

should be avoided in patients receiving amphotericin B

because concomi tant administrat ion may increase

potent ia l for nephrotoxici ty.

*Patients who are not adherent to secondary prophylaxis may be treated with the

regimen above for treatm ent of a first episode of CC.

These combinations are not evidence-based.

Fig. 3. India ink m icroscopy stain demonstrat ing encapsulatedcryptococcal yeasts, some of t hem buddin g.


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Laboratory diagnostic tests for CC

The India i nk test has good sensi t i v ity (80 - 98%)7,21 an d

specifici ty in ARV-nave and fluconazole-nave populations,

but may have lower sensitivi ty in patients who are receiving

fluconazole for other reasons (commonly mucocutaneous

candidiasis), who present early in the course of disease and

who have low fungal burden in the CSF. A negative India ink

test does not exclude th e diagnosis.

CrAg detection by latex agglut ination has excel lent sensitivi ty

and specificity, but is expensive, especially when titres are

perform ed. The test should be perfor med on neat and at least

one ti tred specimen (preferably 1:8 di lution) in order to

exclude fa lse-negat ive resul ts due to the prozone

phenomenon . Use th is test only in the fo l lowing

circumstances:

For all CSF when the India ink test is negative (unless an

al ternat ive d iagnosis has been made e.g. bacter ia l

meningi t is)

For non-CSF specimens such as blood or serum or urine if

CSF is not obtainable.

Cul ture of C. neoformans i s the gold standard for the

diagnosis of CC. Culture may take up to 2 weeks to appear;

therefore keep culture plates for 14 days before reporting

specimens as negative (l iaise with the laboratory service to

ensure that this is done). Laboratories that offer anti fungal

suscept ib i l i ty test ing may wish to preserve cul tures of

C. neoform ansfrom incident cases.

Antif ungal susceptibility t esting of C. neoformans

Antifungal susceptibi l i ty testing requires special ised labo-

ratory services and trained laboratory personnel, both of

which are not often avai lable to routine general hospitalservices. Cl inicians should be w ary of indiscriminate r eporting

of ant i fun gal susceptibi l i ty t esting r esults and should interpret

th ese results w ith special ist con sultation.

Clinical ly rel iable and objective values for interpretation of

susceptibi l i ty testing (MIC breakpoints) of C. neoformans

against fluconazole have not been establ ished; therefore

althou gh t esting can be done, results m ay not be predictive of

cl inical response and out come.

Microbiological resistance to fluconazole may be present

wh en a recurrent isolate of C. neoform anshas a higher M IC (at

least 2 di lut ions) than t he incident isolate w hen th e AFST hasbeen done in parallel (i.e. at the same time), using E-test or

CLSI M27-A2 methodology and where control strains have

been included. Given that AFST can only be done in this

manner after management of the patients recurrent episode

has commenced, AFST results are not expected to impact

significantly on initial m anagement of relapse episodes.

Susceptibi l i ty testing methodology of C. neoformansagainst

amphotericin B is not sufficiently developed for appl icabi l i ty

to the cl inical setting.

COUNSELLING OF PATIENTS DIAGNO SED W ITHCRYPTOCOCCOSIS

Patients, their relatives and caregivers should be counselled

regarding cryptococcosis:

That t he initial t reatment phase wil l last 10 weeks, and

That secondary prophylaxis wi l l be requi red for an

extended period of time.

Clear written instructions regarding the patients medication

schedule should be provided.

All patients who do not know their HIV status should bestrongly advised to undergo testing as part of provider-

initiated testing and counselling (PITC). A diagnosis of CC

represents an opport unit y fo r enrol lm ent int o HIV services. In

the context of ART, patients with cryptococcosis have a

reasonable progno sis for survival.

Sample drugs ( f luconazole, ant i retrovi ra l drugs, co-

trimoxazole) including the dispensed containers and pi l ls are

helpful aids for counsell ing the patient.

Patients who are confused should be counselled when their

level of consciousness has improved, and ideal ly a family

mem ber or caregiver should be involved in the coun sell ing.

CONCURRENT OPPORTUN ISTIC INFECTION S

Patients wit h CC are profoun dly imm unosuppressed and oft en

have concur ren t oppor tun i s t i c i n fec t i ons i nc lud ing

tuberculosis. Cl inicians should ensure that patients who have

symptoms suggestive of TB (fevers, cough, night sweats, loss

of weight) are appropr iate ly invest igated as pulmonary

cryptococcosis may mimic pulmonary TB. Microscopy and

cu l tu re fo r tubercu los i s o f spu tum and o the r c l i n i ca l

specimens should be perform ed wh ere indicated.

RECOM M ENDATION 4: SUPPLEM ENTARYM ANAGM ENT OF CC

1. Counsell ing of pat ients diagnosed with CC

All patients who are diagnosed with CC should be

counselled (once f ul ly con scious) regarding:

The need for compl iance wi t h f luconazole therapy(both consolidation and secondary prop hylaxis)

The u rgen t need fo r H IV test i ng ( i f H IV sta tus

unknow n) and l i f elong ART.

2. Concur ren t oppor tun is t i c i n fec t i ons i nc lud ing

tu berculosis in patient s with CC

Diagnose and t rea t concomi tan t oppor tun i s t i c

infections in patients with CC, particularly pulmonary

and extrapulmonary tuberculosis, pneumocyst is

pneumonia (PCP), bacterial pneumonia, and chronic

diarrhoea. Al l patients with CC should have a chest X-

ray.


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PG 30 NEW AD - ABBOTT


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PG 31 NEW AD - ABBOTT


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PREVENTION OF CC

ART should be init iated aft er patient s have been screened f orth e presence of opportu nistic infection s by cl inical history and

examination, with or without laboratory investigations as

indicated. Screening for CC by perform ing serum CrAg testing

in patients with low CD4 counts and evidence of systemic

i l lness prior to commencement of ART may have a role in

preventin g th e development of CC soon af ter ART initiation 22 - 24

(see below). Primary prevention of CC with fluconazole may

have a l imited role in patients with CD4 counts below 100

cells/l where delays in access to ART are anticipated.25

INITIATION OF ART IN ARV- NAVE CLIENTS W ITH CC

All HIV-positive patients who develop CC are el igible for co-

trimoxazole preventive therapy (CPT) and ART.

Evidence for the optimal timing of ART initiation is not

avai lable: we bel ieve ART is mo st appropriately start ed 2 - 4

weeks after treatment for CC has commenced. Although no

prospective evidence exists in this regard, given these patients

advanced immunosuppression, delaying ART introductionbeyond 4 w eeks to reduce t he risk of IRIS may increase the risk

of morta l i ty . The long in-hospi ta l stay associated wi th

amphotericin B therapy should faci l i tate pre-ART counsell ing,

identi fication of a treatment supporter and early referral to an

ART centre.

Patients who are initiated on ART should be counselled

regarding th e risk of development of IRIS.

If a patient is referred to anoth er faci l i ty f or ART, the need for

fluconazole maintenance therapy should be communicated.

Ant i retrovi ra l regimens including nucleoside and non-

nucleoside reverse transcriptase inhibitors are appropriate.

Caution should be observed when using nevi rapine-

containing ART regimens as fluconazole increases nevirapine

levels and may result in hepatotoxicity with fluconazole co-

administrat ion.

IM M UNE RECONSTITUTION INFLAM M ATORYSYNDROM E

Patients who are receiving ART may develop IRIS related to

i n fe c t i o n w i t h Cryptococcus species in the fo l lowing

scenarios:

Unmasking IRIS occurs in patients not know n t o have CC

who are commenced on ART and develop an incident

episode of CC within the first 3 months of ART. Theseepisodes of CC usually meet t he definit ion f or a diagnosis

of CC (Recommendation 3) and should receive anti fungal

therapy according to Recomm endation 2. Patients wh o are

el igible for ART should have opportunistic infections

excluded; serum CrAg testing may ident i fy pat ients at risk

for unm asking IRIS.

Paradoxical IRIS occurs in patients who have a diagnosis

of CC before star t ing ART and have responded to

anti fungal therapy. The most common presentation of

paradoxical IRIS is recurrent meningitis associated with

raised intracranial pressure, but other manifestations l ike

enlarging cryptococcom as, encephali tis and lymph adenitisare described. Recommendation 5 advises on paradoxical

IRIS.

RECOM M ENDATION 6 : CC IN SPECIAL POPULATIONS

1. Cryptococcosis in the pregnant pat ient

No alterations in th e management of cryptococcosis are

required for treatment of cryptococcosis in pregnancy.

RECOM M ENDATION 5 : THE ROLE OFAN TIRETROVIRAL THERAPY IN PATIENTS W ITH CC

Role of ART

ART is the most effective intervention to treat AIDS, and is

the most potent mechanism to prevent both pr imary and

secondary recurrences of CC. Commence pat ients

(according to relevant local guidel ines) on ART a matter of

urgency.

1. ART

All patients with HIV and CC require ART and co-

tr imoxazole prophylact ic therapy. ART should be

commenced 2 - 4 weeks a f te r in i t i at i on o f an t i fungal

therapy using relevant national guidel ines for drug

regimens and m oni tor ing.

2. Immune reconst i tu t ion inf lammatory syndrome ( IRIS)

and CC

Management of a patient with suspected paradoxical

IRIS requires the fol low ing:

Co n t in u at i o n o f ART

Lumbar puncture to exclude addi t ional pathology, to

obta in an iso late for suscept ib i l i ty test ing to

flucon azole and t o m easure int racranial pressure

CT scan of t he head wh en focal neuro logical signs are

present

Appropr ia te an t i fungal therapy

Cu l tu re -pos i t i ve cases shou ld recei ve t reatm en t

according to Recommendation 2

Cul ture-negat ive cases should cont inue wi th thei r

consol idat ion phase treatment or secondaryprophylaxis (clinicians should ensure adherence) as

appropriate

Ora l ste roid the rapy w i th p redn isone 1 mg/kg dai l y

for at least a week i f symptoms fai l to respond after

appropr iate management of ra ised in tracrania l

pressure and symptomatic treatment. Some patients

require prolonged courses of steroids to control IRIS

manifestations.


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CRYPTOCOCCOSIS IN CHILDREN

Cryptococcosis in chi ldren is uncommon, but does occur with

a bimodal distribution, fi rstly in neonates and young infants

where the mode of acquisition is possibly vertical, and

secondly in school -going and adolescent ch i ldren who

acquired HIV infection in early chi ldhood or inf ancy. The latt er

group presents very similarly to adult CC.

DRUG INTERACTIONSAdministrat ion of f luconazole in pat ients on concurrent

intensive phase TB treatment appears to be a risk factor for

drug-induced hepati tis.26 Patients should be monitored both

cl inical ly and with laboratory testing.

Because of ri fampicin induction of fluconazole metabolism,

some cl inicians consider increasing th e dose of f luconazole by

50% during continuation phase and secondary prophylaxis.

1 . D ru g in f or m at i on

Refer to text below, and Appendix: Amphotericin B

information sheet for cl inical staff

2. Addi t ive drug toxic i t ies, in teract ions and requi red

alterations of dose in patients receiving fluconazole

together wi th ot her ant i - in fect ive agents

Fluconazole is an enzyme inh ibitor and m ay cause levels of

concomitantly administered drugs to increase.

Concurrent

medication

( w it h D ru g i nt er act i on / Req ui red

f luconazole) addit ive t oxicit y alterat ion

Pyrazinamide, Drug - indu ced Non e (clinical

ison iazid hepat it is and laborat ory

moni tor ing i s

indicated)

Rif am picin Redu ced levels Con sider

o f f luconazo le increasing the

secondary

Drug- induced f luconazole

hepat it is prophylaxis

dose by 50%*.

Clinical and

laboratory

moni tor ing i s

indicated

regarding the

potential for

hepatotoxic i ty

Nevirapine Drug- induced None (clin ical

hepat it is m on it or ing

wi th laboratory

invest igat ion i f

indicated).

Some clinicians

wou ld not exceed

a f luconazole

dose o f 400 m g

daily.

*See caveat below.

Although fluconazole is teratogenic, the high mortal i ty

of the condition necessitates optimal management of

the mot her.

2. Fluconazole prophylaxis in w omen of chi ldbearing age

Fluconazole is teratogenic. Women of chi ldbearing age

and potential who require fluconazole in the course of

treatment for other conditions should be counselled

regarding the need for appropriate contraception.

3. Cryptococcosis in paediatric patient s

Cryptococcosis in ch i ldren should be suspected,

diagnosed and t reated according t o guidel ines for adu lts

with the fol lowing exceptions as l isted below:

Anti fungal t reatm ent of CC in paediatr ic pat ients

Induct ion phase: Amphoter ic in B 1 mg/kg/dose iv i for

2 w eeks (relapse episodes should be

t reated fo r 4 - 8 weeks, p re ferabl y

unt i l CSF fungal cult ure is negative).

Adequate hydrat ion dur ing ampho-

tericin B treatment should be main-tained.

Conso l ida t ion phase: Fluconazo le 12 - 15 mg/kg once

daily for a further 8 weeks (the

maximum dose should not exceed

400 mg).

Secondary prophylaxis: Fluconazole 6 - 10 mg/kg once dai ly

for l i f e. In chi ldren over the age of 2

years who have evidence of

susta ined immune reconst i tu t ion

on ART (2 - 6 years old: CD4 percent

> 25%, more than 6 years old: CD4

coun t >200 cel l s/ l ) and who a reasymptomat i c w i th the i r l as t

episode of cryptococcosis having

been more than 12 mon ths

previously, secondary prophylaxis

can be stopped.

M anagem ent of raised intracranial pressure

Recommendations for management of intracranial pressure

in adult s apply to chi ldren (i .e. repeated lum bar punct ures).

For refractory raised intracranial pressure, referral to or

discussion with a specialist centre is advised.

RECOM M ENDATION 7 : DRUG INFORM ATION,TOXICITIES AND INTERACTIONS IN PATIENTS

TREATED FOR CC


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Co-administration of fluconazole with nevirapine increases

nevi rapine levels and consequently the potent ia l for

hepatotoxicity.

DRUG INFORM ATION

Amphotericin B (see also detailed information sheetfor clinical staff in Appendix 1)

1. Dosage and administration

a) Contro l led in fusion over 4 hours of amphoter icin B at

1 mg/kg in 1 l i t re of 5% dextrose water should be g iven

AFTER prehydrat ion wi th 1 l i t re normal sa l ine

containin g 20 mm ol KCl (1 ampoule). A test dose,

previously comm on practice, need not be given i f th e

daily dose is run slowly over the first half hour of

administrat ion.

2. Prevention and management of side- effects

a) Major s ide-effects include renal impai rment due to

renal tubular toxicity, usual ly in the second week of

therapy, hypokalaemia, hypomagnesaemia and renal

tubular acidosis, anaemia, febr i le react ions andchemical phlebitis.

b) Nephrotoxic i ty and e lectro lyte abnormal it ies may be

prevented by avoiding amphotericin B in patients with

renal impai rment, by prehydrat ion, by avoid ing

concurrent use of other nephrotoxins (non-steroidal

anti- inflammatory agents (NSIADs), aminoglycosides

including streptomycin) and by routine administration

of potassium and magnesium supplements.

c) Phlebi t is may be prevented by rotat ion of t he dr ip si te

every 2 - 3 days and by f l ush ing o f l i nes af te r the

amphotericin B infusion is complete.

d) Febri le reactions may be prevented when subsequentdoses of amph otericin B are given by admin istration of

paractetamol 1 g 30 m inutes pr ior to dose. Severe

febri le reaction s may require hydrocort isone 25 mg ivi

at the star t o f t he in fusion.

e) I f nephrotoxic ity occurs, manage as fo l lows:

i ) I f creat in ine increases by 2- f o ld or more, omi t a dose

and/or increase prehydration to 1 l i tre 8-hourly

i i ) I f creat in ine fa i ls to decrease after the above

intervention, stop amphotericin B therapy and use

fluconazole.

Fluconazole1. Dosage and administration .

F luconazole has excel lent b ioavai lab i l i ty when

administered oral ly; intravenous administration is rarely

required. CSF penetration is >8 0% of serum levels.

2. Prevention and management of side- effects

Fluconazole is well tolerated. Patients with renal im-

pairment require dose adjustment according to glom erular

filtration rate (GFR):

GFR 10 - 50 ml /m in, reduce dose by up to 50%

GFR


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Guidelines Cryptococcal Meningitis

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