PatientPatient’’s headache is s headache is our headacheour headache

Princess Margaret HospitalPrincess Margaret HospitalDr. Lo Man Wai / Dr. Tang Hon Dr. Lo Man Wai / Dr. Tang Hon LokLok

88thth Nov 2006Nov 2006

HistoryHistorySM Leung, F/66SM Leung, F/66DM nephropathy, HTDM nephropathy, HTESRF with preESRF with pre--emptive cadaveric renal emptive cadaveric renal transplant done on 19transplant done on 19thth Dec 2003 in mainland Dec 2003 in mainland ChinaChinaPost op no AR, baseline creatinine around Post op no AR, baseline creatinine around 130130µµmol/Lmol/LInitial Initial immunosuppressionimmunosuppression: : TacrolimusTacrolimus 3mg 3mg bdbd, , MMF 250mg MMF 250mg bdbd, , prednisoloneprednisolone 10mg daily10mg dailyChanged to Changed to neoralneoral 125mg 125mg bdbd at post transplant at post transplant 6 months6 months

6 months post transplant (Jun 04)6 months post transplant (Jun 04)

Complained of headache for 2 months in Complained of headache for 2 months in clinicclinicNo vomitingNo vomitingNo focal neurological deficitNo focal neurological deficitNo feverNo feverRelieved by Relieved by paracetamolparacetamol

CT brainCT brain

MRI brainMRI brain

Radiological diagnosisRadiological diagnosisCT brain CT brain -- 0.5 x 1 x 1.8cm convex shape extra0.5 x 1 x 1.8cm convex shape extra--axial enhancing lesion over L frontal region with axial enhancing lesion over L frontal region with mild mild perifocalperifocal edema, edema, ddxddx meningiomameningioma or or abscessabscess

MRI brain (6 weeks later) MRI brain (6 weeks later) ––MultilocularMultilocular extraextra--axial collection (maximum axial collection (maximum dimensions of about 3.5 x 3.5 x 2cm) dimensions of about 3.5 x 3.5 x 2cm) demonstrated in the L frontal lobe compatible demonstrated in the L frontal lobe compatible with with subduralsubdural empyemaempyemaAn underlying rim enhancing cystic nodule An underlying rim enhancing cystic nodule around 1cm in diameter compatible with a brain around 1cm in diameter compatible with a brain abscessabscess

Blood testsBlood tests

WCC 13.0 x 10WCC 13.0 x 1099/L/LUrea 15.8 Urea 15.8 mmolmmol/L, creatinine 140 /L, creatinine 140 umolumol/L/LCRP 37.3 mg/LCRP 37.3 mg/LC2 845 C2 845 ugug/L/LHbA1c 7HbA1c 7--8%8%

Neurosurgical interventionNeurosurgical intervention

CraniectomyCraniectomy with drainage of with drainage of subduralsubduraland brain abscess doneand brain abscess doneThickened Thickened duraldural layer with pus found at layer with pus found at subduralsubdural layer and brainlayer and brainIntraIntra--op USG showed small brain abscessop USG showed small brain abscessPus drained and sent for culturePus drained and sent for culture

Cause of abscess?Cause of abscess?

DuraDura layer histology showed layer histology showed fibroticfibroticabscess wall with granulation tissue abscess wall with granulation tissue containing acute and chronic inflammatory containing acute and chronic inflammatory cellscellsPus for bacterial and AFB smear and Pus for bacterial and AFB smear and culture negativeculture negative

Causes of abscess?Causes of abscess?LP done LP done –– opening pressure 13cm Hopening pressure 13cm H22O clear and O clear and colourlesscolourlessProtein 0.72 g/L, glucose 4.5mmol/L Protein 0.72 g/L, glucose 4.5mmol/L (concomitant blood sugar 8mmol/L)(concomitant blood sugar 8mmol/L)WCC 1/cubic mm, RBC 83/cubic mmWCC 1/cubic mm, RBC 83/cubic mmGram smear, Gram smear, cryptococcalcryptococcal antigen, AFB smear, antigen, AFB smear, bacterial culture bacterial culture ––veveSerology markers: Serology markers: cryptococcalcryptococcal antigen positive antigen positive titretitre = 8, = 8, aspergillusaspergillus fumigatusfumigatus antibody, antibody, toxoplasmatoxoplasma antibody and antibody and histoplasmahistoplasmacapsulatumcapsulatum antibody negativeantibody negative

TreatmentTreatmentMMF was stoppedMMF was stoppedGiven a course of Given a course of ceftriaxoneceftriaxone and and metronidazolemetronidazole, headache subsided, headache subsidedRemained Remained afebrileafebrile all along, CRP all along, CRP normalizednormalizedFU CT brain showed resolved L frontal FU CT brain showed resolved L frontal lobe epidural collection and nonlobe epidural collection and non--specific wall thickening of sphenoid specific wall thickening of sphenoid sinussinusSeen by ENT Seen by ENT –– no signs of nasal / no signs of nasal / aural infectionaural infectionMMF was resumed at 250mg MMF was resumed at 250mg bdbd 1 1 months after dischargemonths after discharge

4 months after 4 months after dischargedischarge……

Recurrence of headacheRecurrence of headache

Admitted for headache for 1 weekAdmitted for headache for 1 weekAssociate with low grade fever and Associate with low grade fever and deliriumdeliriumNo focal neurological deficitNo focal neurological deficitLocal inflammation over previous scalp Local inflammation over previous scalp woundwound

Recurrence of Recurrence of empyemaempyema

CT brain CT brain –– L frontal L frontal subduralsubduralempyemaempyema around 1.3cm widtharound 1.3cm widthTreated conservative with iv Treated conservative with iv ampicillinampicillin, , metronidazolemetronidazole and and cefotaximecefotaximeMMF was stoppedMMF was stopped

Despite 2 weeks antibiotic therapyDespite 2 weeks antibiotic therapy

Increase in drowsinessIncrease in drowsinessPus discharge from old scalp Pus discharge from old scalp woundwoundCT brain CT brain –– enlargement of enlargement of subduralsubdural empyemaempyema over L over L frontal region frontal region Craniotomy done Craniotomy done Multiple pockets of Multiple pockets of subduralsubduralempyemaempyema and brain abscess and brain abscess identified and drainedidentified and drained

Real culprit revealedReal culprit revealedHistology showed broad fungal Histology showed broad fungal hyphaehyphae with with dichotomous branchingdichotomous branchingFungal culture showed Fungal culture showed AspergillusAspergillus fumigatusfumigatusSerum Serum galactomannangalactomannan negativenegativeCefotaximeCefotaxime and and metronidazolemetronidazole stopped stopped AmphotericinAmphotericin B given for 1 week (0.8mg/kg/day)B given for 1 week (0.8mg/kg/day)Changed to iv Changed to iv voriconazolevoriconazole (200mg then (200mg then stepped up to 400mg stepped up to 400mg bdbd because of concomitant because of concomitant dilantindilantin therapy) after discussion with infectious therapy) after discussion with infectious disease teamdisease team

Stormy clinical courseStormy clinical course

Complicated by pneumonia, UTI with Complicated by pneumonia, UTI with septicaemiasepticaemia, DVT required IVC filter , DVT required IVC filter insertion, cardiac arrest successfully insertion, cardiac arrest successfully resuscitated, infected pressure soreresuscitated, infected pressure soreRelatives insisted to continue Relatives insisted to continue immunosuppressantimmunosuppressantCyclosporinCyclosporin A stepped down to 25mg A stepped down to 25mg bdbdand and prednisoloneprednisolone 7.5mg daily7.5mg dailyNo deterioration in renal functionNo deterioration in renal function

After 12 weeksAfter 12 weeksFU CT brain showed no residual FU CT brain showed no residual collectioncollectionWCC and CRP WCC and CRP normalisednormalisedAfebrileAfebrileGCS gradually improved to GCS gradually improved to 15/1515/15Cyclosporine A stepped up to Cyclosporine A stepped up to 100mg/day and 100mg/day and prednisoloneprednisolonestepped down to 5mg daily (C0 stepped down to 5mg daily (C0 level 30, AUC 705)level 30, AUC 705)VoriconazoleVoriconazole stoppedstopped

Just as everything Just as everything seems going wellseems going well……

3 weeks after stopping antifungal 3 weeks after stopping antifungal therapytherapy…………

Small scalp mass developed Small scalp mass developed just next to previous just next to previous craniotomy sitecraniotomy siteBedside aspiration performed Bedside aspiration performed ––fungal culture grew fungal culture grew AspergillusAspergillusfumigatusfumigatusCT brain CT brain –– lentiformlentiform epidural epidural fluid collection (1.9cm) at L fluid collection (1.9cm) at L frontal regionfrontal region

What will you do next?What will you do next?

Antifungal and surgeryAntifungal and surgery

Iv Iv voriconazolevoriconazole 400mg q12h restarted400mg q12h restartedCyclosporinCyclosporin A stepped down to 25mg dailyA stepped down to 25mg dailyIncrease in mental dullness and fever Increase in mental dullness and fever despite treatmentdespite treatmentSecond craniotomy performed with Second craniotomy performed with excision of fungal brain abscess and excision of fungal brain abscess and necrotic tissue donenecrotic tissue done

Despite operative treatmentDespite operative treatment……

CT brain 3 weeks after CT brain 3 weeks after operation showed 2.5cm fluid operation showed 2.5cm fluid attenuation in L frontal lobe attenuation in L frontal lobe compatible with abscesscompatible with abscess

What will you do next?What will you do next?

More antifungalMore antifungal

CaspofunginCaspofungin 70mg daily added 70mg daily added but stopped after 8 weeks but stopped after 8 weeks because of profuse because of profuse diarrhoeadiarrhoeaCT brain showed resolved CT brain showed resolved abscess 2 weeks before abscess 2 weeks before stopping the drugstopping the drugCRP and WCC CRP and WCC normalisednormalisedAfebrileAfebrileVoriconazoleVoriconazole was continuedwas continued

ENT lesionENT lesionFU CT brain also showed FU CT brain also showed collection with calcification in L collection with calcification in L sphenoid sinussphenoid sinusSeen by ENT and suggested L Seen by ENT and suggested L functional functional endoscopicendoscopic sinus sinus surgery under GA to drain surgery under GA to drain abscess abscess Surgery was performed in YCH Surgery was performed in YCH uneventfully in Dec 05uneventfully in Dec 05’’ and and muddy material was drainedmuddy material was drained

End of story?End of story?

3 months after stopping 3 months after stopping caspofungincaspofungin

Noticed to have swelling over the Noticed to have swelling over the scalp with fluctuationscalp with fluctuation

Tapping done and culture showed Tapping done and culture showed recurrence of recurrence of AspergillusAspergillus

CT brain showed a 4cm rimCT brain showed a 4cm rim--enhancing lesion compatible with enhancing lesion compatible with empyemaempyema

What can we do next?What can we do next?

Treatment failureTreatment failureSeen by neurosurgical Seen by neurosurgical –– suggest suggest conservative managementconservative managementPatientPatient’’s relatives insist to continue the s relatives insist to continue the immunosuppressantimmunosuppressantVoriconazoleVoriconazole stopped and stopped and amphotericinamphotericinB triedB triedFU CT brain showed mild increase in FU CT brain showed mild increase in size of the size of the subduralsubdural empyemaempyemaClinically treatment failure, Clinically treatment failure, amphotericinamphotericin B stopped after the 4 B stopped after the 4 week courseweek coursePatient was discharged Patient was discharged

Just as everything Just as everything seems getting worseseems getting worse……

And they live happily togetherAnd they live happily together……PatientPatient’’s conscious state did not s conscious state did not deteriorate after dischargedeteriorate after discharge

Pus discharge from scalp wound, Pus discharge from scalp wound, on daily dressing (still positive on daily dressing (still positive for for AspergillusAspergillus))

Latest CT brain in July 06Latest CT brain in July 06’’showed mild interval resolution showed mild interval resolution of the of the parasagittalparasagittal frontal frontal subduralsubdural empyemaempyema

……with a stable renal functionwith a stable renal function

Last seen in clinic on 18th Oct 2006 (7 Last seen in clinic on 18th Oct 2006 (7 months after declared treatment failure)months after declared treatment failure)

Renal function stable (serum creatinine Renal function stable (serum creatinine 4949µµmol/L), on mol/L), on CsACsA 75mg daily and 75mg daily and prednisoloneprednisolone 10mg daily10mg daily

Relationship between Relationship between immunosuppressant and immunosuppressant and antifungalsantifungals

0

100

200

300

400

1.9.04

1.10.0

4

1.11.0

4

1.12.0

4

1.1.05

1.2.05

1.3.05

1.4.05

1.5.05

Amphotericin B

CsA/day

Prednisolone/day

Antifungal

Voriconazole

200 mg BD

Voriconazole400mg bd

10mg

125mg 150mg 125mg 75mg

7mg

50mg

10mg

MMF 250mg bd

Craniectomy Craniotomy

Relationship between Relationship between immunosuppressant and immunosuppressant and antifungalsantifungals

0

100

200

300

400

1.6.05

1.7.05

1.8.05

1.9.05

1.10.0

5

1.11.0

5

1.12.0

5

1.1.06

1.2.06

1.3.06

Amphotericin B

CsA/day

Prednisolone/day

Antifungal Voriconazole 400 mg BD

Voriconazole400mg bd

5mg

100mg

10mg

25mg

Nil Nil

Caspofungin

Craniotomy

50mg

SummarySummaryF/66 post cadaveric renal transplant presented F/66 post cadaveric renal transplant presented with with aspergillusaspergillus brain abscess 6 months post brain abscess 6 months post transplanttransplant

Treated with Treated with amphotericinamphotericin B, B, voriconazolevoriconazole, , voriconazolevoriconazole and and caspofungincaspofungin combination combination therapy with adjuvant surgical interventiontherapy with adjuvant surgical intervention

Recurrence of brain abscess despite treatmentRecurrence of brain abscess despite treatment

Preserved allograft function with minimal Preserved allograft function with minimal immunosuppressionimmunosuppression

Literature review on Literature review on AspergillusAspergillus infectioninfection

Mycology of Mycology of AspergillusAspergillus

Exist only as mold; not Exist only as mold; not dimorphicdimorphic

SeptateSeptate hyphaehyphae that that form form dichotomusdichotomusbraches (V shaped)braches (V shaped)

The conidia form The conidia form radiating chainsradiating chains

Transmission and pathogenesisTransmission and pathogenesis

Ubiquitous in natureUbiquitous in natureTransmission is by airborne conidiaTransmission is by airborne conidiaColonize and later invade abraded skin, Colonize and later invade abraded skin, wound, burns, cornea, external ear and wound, burns, cornea, external ear and paranasalparanasal sinusessinusesIn In immunocompromisedimmunocompromised host, they will host, they will further invade into lung and other organsfurther invade into lung and other organs

Epidemiology Epidemiology

Prevalence of invasive Prevalence of invasive aspergillosisaspergillosisestimated to be 0.7% among kidney estimated to be 0.7% among kidney transplant recipientstransplant recipientsMost occur within the first 6 months of Most occur within the first 6 months of transplantationtransplantation

Singh N. Program and Abstracts, Focus on Fungal infections 8,March 4-6, 1998, Orlando, Florida

Clinical features of fungal brain Clinical features of fungal brain abscessabscess

Fever (76%)Fever (76%)

Altered mental status (65%)Altered mental status (65%)

HemiplegiaHemiplegia or or hemiparesishemiparesis (35%)(35%)

Cranial nerves abnormalities (29%)Cranial nerves abnormalities (29%)

Seizures, nausea and vomiting, headache Seizures, nausea and vomiting, headache (10(10--20%)20%)

Baddley et al. Clin Transplant 2002: 16: 419-424

Treatment of Treatment of aspergillusaspergillus brain brain abscessabscess

Reversal of Reversal of immunosuppressionimmunosuppression

AntiAnti--fungal therapyfungal therapy

Surgery to Surgery to debridedebride necrotic tissue and to necrotic tissue and to remove infected tissueremove infected tissue

AmphotericinAmphotericin BBA A macrolidmacrolid antibiotic of complex structureantibiotic of complex structureIt acts by binding to fungal cell membranes It acts by binding to fungal cell membranes preferentially and interfere with its permeability preferentially and interfere with its permeability and transport functionand transport functionLipid formulation is the preferred over the Lipid formulation is the preferred over the conventional because it can deliver higher dose conventional because it can deliver higher dose with fewer toxic effectswith fewer toxic effects3 formulations currently marketed: ABLC 3 formulations currently marketed: ABLC ((amphotericinamphotericin B lipid complex), B lipid complex), AmiBisomeAmiBisome((liposomalliposomal amphotericinamphotericin) and ABCD ) and ABCD ((amphotericinamphotericin B colloidal dispersion)B colloidal dispersion)

AmphotericinAmphotericin B B –– side effectsside effectsNephrotoxicityNephrotoxicity, , azotemiaazotemia, renal tubular , renal tubular acidosis, acidosis, nephrocalcinosisnephrocalcinosisHypotension, Hypotension, tachypneatachypnea, fever, chills, , fever, chills, nausea, vomiting, headache, malaisenausea, vomiting, headache, malaise

Suggested dosage Suggested dosage ––ABLC / ABLC / amibisomeamibisome 5mg/kg/day for 3 to 6 5mg/kg/day for 3 to 6 months, in critically ill patients months, in critically ill patients 10mg/kg/day up to 15mg/kg/day10mg/kg/day up to 15mg/kg/day

AmphotericinAmphotericin B B ––precautions for renal physicianprecautions for renal physician

Renal impairment: total daily dose Renal impairment: total daily dose decrease 50% or given on alternate daysdecrease 50% or given on alternate daysImportant drug interactions:Important drug interactions:Increase Increase nephrotoxicitynephrotoxicity with cyclosporine with cyclosporine or or aminoglycosideaminoglycosidePotentiationPotentiation of hypokalaemia with of hypokalaemia with corticosteroidscorticosteroids

VoriconazoleVoriconazole

New New azoleazole groupgroupAction by inhibit the fungal P450 enzymes Action by inhibit the fungal P450 enzymes for the synthesis of the main sterol in cell for the synthesis of the main sterol in cell membrane, thus inhibit fungal cell membrane, thus inhibit fungal cell membrane formationmembrane formationFungistaticFungistatic against all fungi including against all fungi including resistant strains, and is fungicidal against resistant strains, and is fungicidal against aspergillusaspergillus

VoriconazoleVoriconazole –– side effectsside effectsVisual changesVisual changesPhotophobiaPhotophobiaColourColour changeschangesChange in visual acuityChange in visual acuity

Suggested dosage:Suggested dosage:Loading dose 6mg/kg every 12 hours for 2 Loading dose 6mg/kg every 12 hours for 2 doses; followed by maintenance dose of 4mg/kg doses; followed by maintenance dose of 4mg/kg every 12 hoursevery 12 hoursRenal impairment Renal impairment –– no need to reduce the dose no need to reduce the dose but maintenance dose should be in oral formbut maintenance dose should be in oral form

VoriconazoleVoriconazole –– precautions to renal precautions to renal physiciansphysicians

VoriconazoleVoriconazole increases the serum levels increases the serum levels and effects of cyclosporine, dosage of and effects of cyclosporine, dosage of cyclosporine should be reduced by half cyclosporine should be reduced by half and level monitored closelyand level monitored closelyVoriconazoleVoriconazole will also increase the serum will also increase the serum levels of levels of sirolimussirolimus and and tacrolimustacrolimus

CaspofunginCaspofungin

An An echinocandinsechinocandins derivativederivativeAction on signal transduction essential for fungal Action on signal transduction essential for fungal cell wall assemblycell wall assembly

Suggested dosage:Suggested dosage:70mg on day 1 then 50mg/day subsequently70mg on day 1 then 50mg/day subsequentlyDuration of treatment determined by patient Duration of treatment determined by patient status and clinical response (suggested to stop status and clinical response (suggested to stop drug 2 weeks after culture negative)drug 2 weeks after culture negative)

CaspofunginCaspofungin –– side effectsside effects

Well toleratedWell toleratedElevation in ALP and Elevation in ALP and transaminasestransaminasesFever, chills, headacheFever, chills, headacheNausea, vomiting, abdominal pain and Nausea, vomiting, abdominal pain and diarrhoeadiarrhoea

CaspofunginCaspofungin –– precautions for precautions for renal physiciansrenal physicians

Concomitant use with cyclosporine may Concomitant use with cyclosporine may increase increase caspofungincaspofungin concentration and concentration and cause elevation in hepatic cause elevation in hepatic transaminasetransaminaseCaspofunginCaspofungin may decrease blood may decrease blood concentration of concentration of tacrolimustacrolimusNo specific dosage modification is required No specific dosage modification is required for renal impairmentfor renal impairment

Which one is better?Which one is better?

VoriconazoleVoriconazole is drug of choice for treatment of is drug of choice for treatment of invasive invasive aspergillosusaspergillosusIn a randomized open label of 277 patients with In a randomized open label of 277 patients with confirmed or probable confirmed or probable aspergillosisaspergillosisUnderlying Underlying allogenicallogenic haematopoietichaematopoietic cell cell transplantation, acute transplantation, acute leukaemialeukaemia or other or other haematologichaematologic diseasesdiseases144 treated with 144 treated with voriconazolevoriconazole and 133 treated and 133 treated with with amphotericinamphotericin B B

Herbrecht et al: NEJM 2002; 347: 408-415

Which one is better?Which one is better?VoriconazoleVoriconazole 6mg/kg 6mg/kg bdbd on day 1 then 4mg/kg on day 1 then 4mg/kg bdbdfor 1 week then oral 200mg for 1 week then oral 200mg bdbdAmphotericinAmphotericin B B deoxycholatedeoxycholate (conventional) 1 to (conventional) 1 to 1.5mg/kg1.5mg/kgAt 12 weeks, At 12 weeks, voriconazolevoriconazole group group vsvs amphotericinamphotericinB group: B group: Successful outcome: 52.8% Successful outcome: 52.8% vsvs 31.6% (95% CI 31.6% (95% CI difference 10.4 to 34.9)difference 10.4 to 34.9)Survival rate: 70.8% Survival rate: 70.8% vsvs 57.9% (95% CI hazard 57.9% (95% CI hazard ratio 0.40 to 0.88)ratio 0.40 to 0.88)

Herbrecht et al: NEJM 2002; 347: 408-415

Which one is better?Which one is better?

CaspofunginCaspofungin should not be used for should not be used for primary therapy because of lack of dataprimary therapy because of lack of data

It can be used for those who cannot It can be used for those who cannot tolerate or refractory to primary therapytolerate or refractory to primary therapy

It can also be used in combination therapyIt can also be used in combination therapy

Combination therapyCombination therapy

The role of combination antifungal therapy The role of combination antifungal therapy as either initial or salvage therapy is as either initial or salvage therapy is unproved since the benefit must be unproved since the benefit must be weighed against the increase in toxicityweighed against the increase in toxicity

There are retrospective studies showing a There are retrospective studies showing a marginal benefits of addition of marginal benefits of addition of caspofungincaspofungin on top of on top of amphotericinamphotericin B B therapytherapy

Aliff et al. Cancer 2003; 97: 1563

Kontoyiannis et al. Cancer 2003; 98:292

Combination therapyCombination therapy

Data on combination of Data on combination of voriconazolevoriconazole and and caspofungincaspofungin seems more promisingseems more promisingIn one retrospective study of 47 patients In one retrospective study of 47 patients with progressive with progressive aspergillosisaspergillosis despite despite amphotericinamphotericin B therapyB therapy31 received 31 received voriconazolevoriconazole only and 16 only and 16 received received voriconazolevoriconazole + + caspofungincaspofunginA significant lower rate of mortality (odds A significant lower rate of mortality (odds ratio 0.28) was found at 3 monthsratio 0.28) was found at 3 months

Marr et al. Clin Infect Dis 2004; 39: 797

Combination therapyCombination therapyAnother Another prosepectiveprosepective study involving 87 patients with study involving 87 patients with SOT suffering from invasive SOT suffering from invasive aspergillosisaspergillosis

47 patients received lipid formulation of 47 patients received lipid formulation of amphotericinamphotericin B B compared with 40 patients received compared with 40 patients received caspofungincaspofungin and and voriconazolevoriconazole as primary therapyas primary therapy

Survival rate at 90 days was better for those who Survival rate at 90 days was better for those who received combination therapy (67.5% received combination therapy (67.5% vsvs 51%)51%)

Singh et al. Transplantation 2006; 81-230

Current recommendationCurrent recommendationDecrease the degree of Decrease the degree of immunosuppressionimmunosuppressionwhenever possiblewhenever possible

VoriconazoleVoriconazole as initial therapyas initial therapy

Combination therapy for those who do not Combination therapy for those who do not respond to initial therapyrespond to initial therapy

Duration of therapy is dependent upon the Duration of therapy is dependent upon the patientpatient’’s underlying disease and respond to s underlying disease and respond to therapytherapy

Drug bill Drug bill –– only counting antifungalonly counting antifungal

VoriconazoleVoriconazole 400mg 400mg bdbd = $1366= $1366Total 9 months = $368,820Total 9 months = $368,820

CaspofunginCaspofungin 70mg $412070mg $4120Total 8 weeks = $230,720Total 8 weeks = $230,720

Grand total = $599,540 (HKD)Grand total = $599,540 (HKD)

EndEndThank youThank you