Some Problems in Treating Cryptococcal Meningitis-A Serial Case Report - A Mawuntu

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 moNo meningeal signs; no papilledema; left CN. VI & left peripheral CN. VII palsyLab: CD4+ abs: 29; Brain CT: multiple small nodular lesions in left & right parietal lobesLumbar puncture (LP): high opening pressure; India ink staining:(++) cryptococcus; culture (+)AmBD 0,7 mg/kgBW/day iv + fluconazole 150 mg bid oral for 14 daysLP 14-th day: >27 cmH2O; India ink (+); culture (+) continue txLP 21-st day: 25 cmH2O; India ink (+); culture (-) continue txLP 28-th day: 10 cmH2O; 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 daysAlert, normal motor strength, left CN. VI palsy, no meningeal signsOral thrush, genital ulcer, tattooLumbar puncture (LP): high opening pressure; India ink staining:(++) cryptococcus; culture (+), cryptococcus antigen (+) titer 1/300AmBD 0,7 mg/kgBW/day iv for 14 days repeat LP Culture still (+) continue tx for 14 days clinically improvedRepeat LP culture (+), antigen shifted to oral fluconazole200 mg bid for 1 week dischargedLeft CN. VI palsy improved after 1-st LPTransient elevation of ur & cr improved with good hydrationAlso 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 ARV3 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 fluconazoledischarged

Neuro exam was unremarkableFluconazole 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: 24Fluconazole 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, 769–773.

SymptomsHeadache (73 – 81%)Fever (62 – 88%)Asthenia (38 – 76%)Acute/ sub acute behavioral change (18 – 28%)Nausea & vomiting (8 – 42%)Photophobia (19%)

SignsNeck stiffnessPapilledemaCranial nerves palsy & other focal neurological deficitsAltered 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, 769–773.

In all 3 cases:severe headache + fever DD w/ TB meningitisNo meningeal signs minimal inflammatory reactionNo papilledema

Case 1 & 2: CN palsy raised ICP

Lumbar Puncture & CSF AnalysisRaised opening pressure poor prognosis; cryptococcal meningitis 250 mmH20.CSF analysis: AIDS minimal

India Ink StainingIdentify microorganism diagnosis!!!

CSF CulturesUsed as diagnostic method even in normal CSS analysis

Immunologic TestCryptococcus antigen detection high specificity

Brief ReviewAdvised by many literatures effective in treating cryptococcal infectionAdminister carefully toxicity & adverse effectsToxicity: acute & chronicMany 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, hypotensionCould be reduced by slowing infusion rate/ daily dosePremedication: antipyretics, meperidine, corticosteroid.

Chronic:Most important renal impairment: mild azotemiarenal 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.

• Test dose on 1‐st day w/ 1mg AmBD solution in 350 cc D5 as iv infusion for 4 h. • Continue on first day w/ 0,3 mg/kgBW AmBD in D5 as iv infusion for 6 h.• Second day and forth: AmBD 0,7 – 1 mg/KgBW in D5 as iv infusion 6 h/ 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, & FluconazoleAmphotericin B + flucytosine faster CSF sterility flucytosine not available in hereAmphotericin B + fluconazole theoretically not sinergistic AmB continued w/ fluconazoleSome 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 +/- fluconazoleCase 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 examinationAlthough has unpleasant side effects AmBshould 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 chanceMost possible drug problem storage & administration technique doseShould understand proper knowledge in storing & administering drug

Case 3:Sterile after 1 mo AmBD shifted to fluconazole

Related with poor prognosis if not treated immediatelyTx:

LPLumbal drainageManitol, 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 DiagnosticTherapeutic headache improved, neurological deficits improved, all 3 survived Consider serial LP

ARV administration in acute opportunistic infection (OI) special considerationNo 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 functionFasten recoveryLower secondary opportunistic infection

Negative:Impaired absorption reduced drug level drug resistanceMixed toxicity manifestation of ARV, drug for OI, or clinical manifestation of diseaseDrug interactionImpaired renal & liver function

difficulty in posologyIRIS

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 haven’t been precisely defined fever + worsening of the clinical manifestations of the underlying OIMany 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/ ARVARV 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 analysisUseful ancillary procedure: LP, CSF analysis, India ink staining, culture, serologyTherapy: AmBD +/- fluconazoleSerial LP diagnostic & therapeutic modalityFollow 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