ARTHUR H.P.

MAWUNTU, ASTRA
DEA SIMANUNGKALIT, CORRY N.
MAHAMA, IRAWATI MAYSAM,
DARMA IMRAN
Cryptococcal meningitis (CM) mortality remains high
even in developed countries.
RSCM: 304 AIDS pts with CNS infection (Jan 2004 Jan
2007); 10,2% CM 45% died.
29 yo, , HIV (+), severe headache, intermittent fever, diplopia since
3 mo
No meningeal signs; no papilledema; left CN. VI & left peripheral
CN. VII palsy
Lab: CD4
+
abs: 29; Brain CT: multiple small nodular lesions in left &
right parietal lobes
Lumbar puncture (LP): high opening pressure; India ink staining:
(++) cryptococcus; culture (+)
AmBD 0,7 mg/kgBW/day iv + fluconazole 150 mg bid oral for 14
days
LP 14-th day: >27 cmH
2
O; India ink (+); culture (+) continue tx
LP 21-st day: 25 cmH
2
O; India ink (+); culture (-) continue tx
LP 28-th day: 10 cmH
2
O; India ink (+); culture (-) shift to oral
fluconazole 200 mg bid discharged.
Axial postcontrast Brain CT scan from Patient 1.
Multiple small nodular lesions in both parietal lobes
35 yo, , HIV (+) since 3 years ago, severe headache & fever since
7 days
Alert, normal motor strength, left CN. VI palsy, no meningeal signs
Oral thrush, genital ulcer, tattoo
Lumbar puncture (LP): high opening pressure; India ink staining:
(++) cryptococcus; culture (+), cryptococcus antigen (+) titer 1/300
AmBD 0,7 mg/kgBW/day iv for 14 days repeat LP Culture still
(+) continue tx for 14 days clinically improved
Repeat LP culture (+), antigen shifted to oral fluconazole
200 mg bid for 1 week discharged
Left CN. VI palsy improved after 1-st LP
Transient elevation of ur & cr improved with good hydration
Also received cotrimoxazole for TE prophylaxis
India ink staining (left) and CSF culture (right) from Patient 2.
Department of Paracytology FMUI
22 yo, , HIV (+) since 6 month ago, pulsating headache since
2 days
5 mo ago: started ARV
3 mo ago: Admitted with severe headache & fever. Neurology exam
was unremarkable. Lab: CD4
+
abs: 116 (14%). LP: high opening
pressure; India ink staining: (+) cryptococcus; culture (+)
AmBD + fluconazole for 1 mo & stop ARV fluconazole
discharged
Neuro exam was unremarkable
Fluconazole was continued with oral analgesic; perform
complete peripheral blood study, ALT/AST, ur/cr, CXR, & CD4
+
1 mo after: Headache was improved. Neuro exam was
unremarkable. Lab: CD4
+
abs: 24
Fluconazole was continued, ARV was postponed
Meningitis most common manifestation
Important DD TB meningitis!!!
Bicanic T, Harrison TS. Cryptococcal meningitis. British Medical Bulletin. 2004;72:99 118.
Mwaba P. Mwansa J, Chintu C et al. (2001) Clinical presentation, natural history, and cumulative death rates of 230
adults with primary cryptococcal meningitis in Zambian AIDS patients treated under local conditions. Postgrad Med J,
77, 769773.
Symptoms
Headache (73 81%)
Fever (62 88%)
Asthenia (38 76%)
Acute/ sub acute behavioral
change (18 28%)
Nausea & vomiting (8 42%)
Photophobia (19%)
Signs
Neck stiffness
Papilledema
Cranial nerves palsy & other focal
neurological deficits
Altered consciousness
Symptoms & Signs of Cryptococcal Meningitis
Mwaba P. Mwansa J, Chintu C et al. (2001) Clinical presentation, natural history, and cumulative death rates of 230 adults with
primary cryptococcal meningitis in Zambian AIDS patients treated under local conditions. Postgrad Med J, 77, 769773.
In all 3 cases:
severe headache + fever DD w/ TB meningitis
No meningeal signs minimal inflammatory reaction
No papilledema
Case 1 & 2: CN palsy raised ICP
Lumbar Puncture & CSF Analysis
Raised opening pressure poor prognosis;
cryptococcal meningitis 250 mmH
2
0.
CSF analysis: AIDS minimal
India Ink Staining
Identify microorganismdiagnosis!!!
CSF Cultures
Used as diagnostic method even in normal CSS
analysis
Immunologic Test
Cryptococcus antigen detection high specificity
Brief Review
Advised by many literatures effective in treating
cryptococcal infection
Administer carefully toxicity & adverse effects
Toxicity: acute & chronic
Many are still reluctant in using this drug
Casadevall A, Perfect JR. Cryptococcus neoformans. Therapy of cryptoccocosis. Washington DC: American Society
of Microbiology, 1998. p. 457 518.
Sheppard D, Lampiris HW. Antifungal agents. In: Katzung BG. Basic & clinical pharmacology 9-th ed. Boston:
McGraw-Hill, 2004. p. 792 800.
Redmond A, Dancer C, Woods ML. Fungal infections of the central nervous system: a review of fungal pathogens and
treatment. Neurology India. 2007;55(3):251 9.
Imran D. Kriptokokosis. Dalam: Yunihastuti E, Djauzi S, Djoerban Z (editor). Infeksi oportunistik pada AIDS. Jakarta:
Balai Penerbit FKUI, 2005. hal. 27 32.
Acute:
Occurred in almost every patient.
Fever, chill, muscle spasm,
hypotension
Could be reduced by slowing
infusion rate/ daily dose
Premedication: antipyretics,
meperidine, corticosteroid.
Chronic:
Most important renal
impairment: mild azotemia
renal failure that requires dialysis.
Nephrotoxicity: RTA + K & Mg
loss from urine.
NS infusion could reduced
nephrotoxicity.
Sheppard D, Lampiris HW. Antifungal agents. In: Katzung BG. Basic & clinical pharmacology 9-th ed. Boston: McGraw-Hill, 2004.
p. 792 800.
Testdoseon1stdayw/1mgAmBD solutionin350ccD5asivinfusionfor4h.
Continueonfirstdayw/0,3mg/kgBW AmBD inD5asivinfusionfor6h.
Seconddayandforth:AmBD 0,7 1mg/KgBW inD5asivinfusion6h/day.
AmBD administration according to Richardson & Jones
(2001)
Yunihastuti E, Djauzi S, Djoerban Z (editor). Infeksi oportunistik pada AIDS. Lampiran 2. Jakarta: Balai Penerbit FKUI, 2005. hal.
27 32.
Adverse drug reaction from Amphotericin B
Combination of Amphotericin B, Flucytosine, &
Fluconazole
Amphotericin B + flucytosine faster CSF
sterility flucytosine not available in here
Amphotericin B + fluconazole theoretically
not sinergistic AmB continued w/ fluconazole
Some study AmB + fluconazole have positive
interaction
Larsen RA, Bauer M, Thomas AM, Graybill JR. Amphotericin B and fluconazole for cryptococcal meningitis.
Antimicrobial agents and chemotherapy. 2004;48(3):985 91.
Imran D. Kriptokokosis. Dalam: Yunihastuti E, Djauzi S, Djoerban Z (editor). Infeksi oportunistik pada AIDS. Jakarta:
Balai Penerbit FKUI, 2005. hal. 27 32.
Scharz P, Guilhem J, Dromer F, Lortholary O, Dannaoui E. Combination of amphotericin B with flucytosine is active in
vitro against flucytosine-resistant isolates of Cryptococcus neoformans. Antimicrobial agents anf chemotherapy.
2007;51(1):383 5.
Beginning: all received AmBD +/- fluconazole
Case 1:
Adverse effect hypoNa & hypoK, no renal impairment
transient & tolerable
Case 2:
Adverse effect nausea, hypoNa, renal impairment
transient & tolerable
Important monitor adverse effect w/ clinical
& laboratory examination
Although has unpleasant side effects AmB
should be given in cryptococcal cases
Case 1:
India ink (+) & culture (-) non functional cells
Case 2:
India ink staining & culture still (+) after 3-rd LP w/
proper AmBD ??? Resistance? small chance
Most possible drug problem storage &
administration technique dose
Should understand proper knowledge in storing &
administering drug
Case 3:
Sterile after 1 mo AmBD shifted to fluconazole
Related with poor prognosis if not treated
immediately
Tx:
LP
Lumbal drainage
Manitol, asetazolamide ???
Imran D. Kriptokokosis. Dalam: Yunihastuti E, Djauzi S, Djoerban Z (editor). Infeksi oportunistik pada AIDS. Jakarta:
Balai Penerbit FKUI, 2005. hal. 27 32.
Pau AK, Brooks JT. Editors. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults
and adolescents. DHHS Panel on Guidelines for the Prevention and Treatment of Opportunistics Infections in HIV-
Infected Adolescents. 18 June 2008.
LP was conducted in all cases
Diagnostic
Therapeutic headache improved, neurological deficits
improved, all 3 survived
Consider serial LP
ARV administration in acute opportunistic
infection (OI) special consideration
No effective drug for cryptococcosis prophylaxis
if possible, administer ARV if CD4
+
<200
Pau AK, Brooks JT. Editors. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults
and adolescents. DHHS Panel on Guidelines for the Prevention and Treatment of Opportunistics Infections in HIV-
Infected Adolescents. 18 June 2008.
Positive:
Improve immune function
Fasten recovery
Lower secondary opportunistic
infection
Negative:
Impaired absorption reduced
drug level drug resistance
Mixed toxicity manifestation of
ARV, drug for OI, or clinical
manifestation of disease
Drug interaction
Impaired renal & liver function
difficulty in posology
IRIS
Benefit vs Risk of Starting ARV in Acute OI
Pau AK, Brooks JT. Editors. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults
and adolescents. DHHS Panel on Guidelines for the Prevention and Treatment of Opportunistics Infections in HIV-
Infected Adolescents. 18 June 2008.
IRIS Manifestations havent been precisely
defined fever + worsening of the clinical
manifestations of the underlying OI
Many patients IRIS in 4 8 weeks after
initiation of ARV, especially if they have high
viral load & very low CD4
+
Pau AK, Brooks JT. Editors. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults
and adolescents. DHHS Panel on Guidelines for the Prevention and Treatment of Opportunistics Infections in HIV-
Infected Adolescents. 18 June 2008.
Murdoch DM, Venter WDF, Van Rie A, Feldman C. Immune reconstitution inflammatory syndrome (IRIS): review of
common infectious manifestations and treatment options. AIDS research and therapy. 2007; 4:9.
Case 3:
Developed cryptococcal meningitis after 2 mo w/ ARV
ARV was postponed some experts advice to postpone
ARV minimal 1 mo after OI treatment
No criteria about when to start ARV in acute OI
Consider the degree of immunosupression, availability &
feasibility of effective OI treatment, drug interaction,
overlapping drug toxicity, adherence
Symptoms & signs obscure suspected CM
always DD w/ TB meningitis LP + CSF analysis
Useful ancillary procedure: LP, CSF analysis,
India ink staining, culture, serology
Therapy: AmBD +/- fluconazole
Serial LP diagnostic & therapeutic modality
Follow up: sequels, new OI, drug toxicity,
initiation of ARV & IRIS, adherence
Tribute to my dearest uncle, the late Sanny Tatimu, for his wonderful love and care in my life
Unique sea creatures, underwater scenery from Lembeh strait, North Sulawesi