guidelines cryptococcal meningitis
TRANSCRIPT
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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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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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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 ld- bearing 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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