Patient s s headache is our headache

Transcription

1 History Patient s s headache is our headache Princess Margaret Hospital Dr. Lo Man Wai / Dr. Tang Hon Lok 8 th Nov 2006 SM Leung, F/66 DM nephropathy, HT ESRF with pre-emptive emptive cadaveric renal transplant done on 19 th Dec 2003 in mainland China Post op no AR, baseline creatinine around 130µmol/L Initial immunosuppression: tacrolimus 3mg bd, MMF 250mg bd, prednisolone 10mg daily Changed to neoral 125mg bd at post transplant 6 months 6 months post transplant (Jun 04) CT brain Complained of headache for 2 months in clinic No vomiting No focal neurological deficit No fever Relieved by paracetamol MRI brain Radiological diagnosis CT brain x 1 x 1.8cm convex shape extra- axial enhancing lesion over L frontal region with mild perifocal edema, ddx meningioma or abscess MRI brain (6 weeks later) Multilocular extra-axial axial collection (maximum dimensions of about 3.5 x 3.5 x 2cm) demonstrated in the L frontal lobe compatible with subdural empyema An underlying rim enhancing cystic nodule around 1cm in diameter compatible with a brain abscess 1

2 Blood tests WCC 13.0 x 10 9 /L Urea 15.8 mmol/l, creatinine 140 umol/l CRP 37.3 mg/l C2 845 ug/l HbA1c 7-8% 7 Neurosurgical intervention Craniectomy with drainage of subdural and brain abscess done Thickened dural layer with pus found at subdural layer and brain Intra-op USG showed small brain abscess Pus drained and sent for culture Cause of abscess? Dura layer histology showed fibrotic abscess wall with granulation tissue containing acute and chronic inflammatory cells Pus for bacterial and AFB smear and culture negative Causes of abscess? LP done opening pressure 13cm H 2 O clear and colourless Protein 0.72 g/l, glucose 4.5mmol/L (concomitant blood sugar 8mmol/L) WCC 1/cubic mm, RBC 83/cubic mm Gram smear, cryptococcal antigen, AFB smear, bacterial culture ve Serology markers: cryptococcal antigen positive titre = 8, aspergillus fumigatus antibody, toxoplasma antibody and histoplasma capsulatum antibody negative Treatment MMF was stopped Given a course of ceftriaxone and metronidazole,, headache subsided Remained afebrile all along, CRP normalized FU CT brain showed resolved L frontal lobe epidural collection and non- specific wall thickening of sphenoid sinus Seen by ENT no signs of nasal / aural infection MMF was resumed at 250mg bd 1 months after discharge 2

3 Recurrence of headache 4 months after discharge Admitted for headache for 1 week Associate with low grade fever and delirium No focal neurological deficit Local inflammation over previous scalp wound Recurrence of empyema CT brain L frontal subdural empyema around 1.3cm width Treated conservative with iv ampicillin, metronidazole and cefotaxime MMF was stopped Despite 2 weeks antibiotic therapy Increase in drowsiness Pus discharge from old scalp wound CT brain enlargement of subdural empyema over L frontal region Craniotomy done Multiple pockets of subdural empyema and brain abscess identified and drained 3

4 Real culprit revealed Histology showed broad fungal hyphae with dichotomous branching Fungal culture showed Aspergillus fumigatus Serum galactomannan negative Cefotaxime and metronidazole stopped Amphotericin B given for 1 week (0.8mg/kg/day) Changed to iv voriconazole (200mg then stepped up to 400mg bd because of concomitant dilantin therapy) after discussion with infectious disease team Stormy clinical course Complicated by pneumonia, UTI with septicaemia,, DVT required IVC filter insertion, cardiac arrest successfully resuscitated, infected pressure sore Relatives insisted to continue immunosuppressant Cyclosporin A stepped down to 25mg bd and prednisolone 7.5mg daily No deterioration in renal function After 12 weeks FU CT brain showed no residual collection WCC and CRP normalised Afebrile GCS gradually improved to 15/15 Cyclosporine A stepped up to 100mg/day and prednisolone stepped down to 5mg daily (C0 level 30, AUC 705) Voriconazole stopped 4

5 Just as everything seems going well 3 weeks after stopping antifungal therapy Small scalp mass developed just next to previous craniotomy site Bedside aspiration performed fungal culture grew Aspergillus fumigatus CT brain lentiform epidural fluid collection (1.9cm) at L frontal region Antifungal and surgery What will you do next? Iv voriconazole 400mg q12h restarted Cyclosporin A stepped down to 25mg daily Increase in mental dullness and fever despite treatment Second craniotomy performed with excision of fungal brain abscess and necrotic tissue done Despite operative treatment CT brain 3 weeks after operation showed 2.5cm fluid attenuation in L frontal lobe compatible with abscess What will you do next? 5

6 More antifungal Caspofungin 70mg daily added but stopped after 8 weeks because of profuse diarrhoea CT brain showed resolved abscess 2 weeks before stopping the drug CRP and WCC normalised Afebrile Voriconazole was continued ENT lesion FU CT brain also showed collection with calcification in L sphenoid sinus Seen by ENT and suggested L functional endoscopic sinus surgery under GA to drain abscess Surgery was performed in YCH uneventfully in Dec 05 and muddy material was drained 3 months after stopping caspofungin End of story? Noticed to have swelling over the scalp with fluctuation Tapping done and culture showed recurrence of Aspergillus CT brain showed a 4cm rim- enhancing lesion compatible with empyema Treatment failure What can we do next? Seen by neurosurgical suggest conservative management Patient s s relatives insist to continue the immunosuppressant Voriconazole stopped and amphotericin B tried FU CT brain showed mild increase in size of the subdural empyema Clinically treatment failure, amphotericin B stopped after the 4 week course Patient was discharged 6

7 And they live happily together Just as everything seems getting worse Patient s s conscious state did not deteriorate after discharge Pus discharge from scalp wound, on daily dressing (still positive for Aspergillus) Latest CT brain in July 06 showed mild interval resolution of the parasagittal frontal subdural empyema with a stable renal function Relationship between immunosuppressant and antifungals Last seen in clinic on 18th Oct 2006 (7 months after declared treatment failure) Renal function stable (serum creatinine 49µmol/L), on CsA 75mg daily and prednisolone 10mg daily CsA/day Prednisolone /day Craniectomy Craniotomy 125mg 150mg 125mg 75mg 10mg 7mg MMF 250mg bd AmphotericinB 50mg 10mg Antifungal Voriconazole 400mg bd Voriconazole 200 mg BD Relationship between immunosuppressant and antifungals Summary CsA/day Prednisolone /day Antifungal Craniotomy 50mg 100mg 5mg Nil Voriconazole 400mg bd Caspofungin 25mg Voriconazole 400 mg BD mg Nil AmphotericinB F/66 post cadaveric renal transplant presented with aspergillus brain abscess 6 months post transplant Treated with amphotericin B, voriconazole, voriconazole and caspofungin combination therapy with adjuvant surgical intervention Recurrence of brain abscess despite treatment Preserved allograft function with minimal immunosuppression 7

8 Mycology of Aspergillus Literature review on Aspergillus infection Exist only as mold; not dimorphic Septate hyphae that form dichotomus braches (V shaped) The conidia form radiating chains Transmission and pathogenesis Ubiquitous in nature Transmission is by airborne conidia Colonize and later invade abraded skin, wound, burns, cornea, external ear and paranasal sinuses In immunocompromised host, they will further invade into lung and other organs Epidemiology Prevalence of invasive aspergillosis estimated to be 0.7% among kidney transplant recipients Most occur within the first 6 months of transplantation Singh N. Program and Abstracts, Focus on Fungal infections 8,March 4-6, 1998, Orlando, Florida Clinical features of fungal brain abscess Fever (76%) Altered mental status (65%) Hemiplegia or hemiparesis (35%) Cranial nerves abnormalities (29%) Seizures, nausea and vomiting, headache (10-20%) Treatment of aspergillus brain abscess Reversal of immunosuppression Anti-fungal therapy Surgery to debride necrotic tissue and to remove infected tissue Baddley et al. ClinTransplant 2002: 16:

9 Amphotericin B A macrolid antibiotic of complex structure It acts by binding to fungal cell membranes preferentially and interfere with its permeability and transport function Lipid formulation is the preferred over the conventional because it can deliver higher dose with fewer toxic effects 3 formulations currently marketed: ABLC (amphotericin B lipid complex), AmiBisome (liposomal amphotericin) ) and ABCD (amphotericin B colloidal dispersion) Amphotericin B side effects Nephrotoxicity, azotemia,, renal tubular acidosis, nephrocalcinosis Hypotension, tachypnea,, fever, chills, nausea, vomiting, headache, malaise Suggested dosage ABLC / amibisome 5mg/kg/day for 3 to 6 months, in critically ill patients 10mg/kg/day up to 15mg/kg/day Amphotericin B precautions for renal physician Renal impairment: total daily dose decrease 50% or given on alternate days Important drug interactions: Increase nephrotoxicity with cyclosporine or aminoglycoside Potentiation of hypokalaemia with corticosteroids Voriconazole New azole group Action by inhibit the fungal P450 enzymes for the synthesis of the main sterol in cell membrane, thus inhibit fungal cell membrane formation Fungistatic against all fungi including resistant strains, and is fungicidal against aspergillus Voriconazole side effects Visual changes Photophobia Colour changes Change in visual acuity Suggested dosage: Loading dose 6mg/kg every 12 hours for 2 doses; followed by maintenance dose of 4mg/kg every 12 hours Renal impairment no need to reduce the dose but maintenance dose should be in oral form Voriconazole precautions to renal physicians Voriconazole increases the serum levels and effects of cyclosporine, dosage of cyclosporine should be reduced by half and level monitored closely Voriconazole will also increase the serum levels of sirolimus and tacrolimus 9

10 Caspofungin An echinocandins derivative Action on signal transduction essential for fungal cell wall assembly Suggested dosage: 70mg on day 1 then 50mg/day subsequently Duration of treatment determined by patient status and clinical response (suggested to stop drug 2 weeks after culture negative) Caspofungin side effects Well tolerated Elevation in ALP and transaminases Fever, chills, headache Nausea, vomiting, abdominal pain and diarrhoea Caspofungin precautions for renal physicians Concomitant use with cyclosporine may increase caspofungin concentration and cause elevation in hepatic transaminase Caspofungin may decrease blood concentration of tacrolimus No specific dosage modification is required for renal impairment Which one is better? Voriconazole is drug of choice for treatment of invasive aspergillosus In a randomized open label of 277 patients with confirmed or probable aspergillosis Underlying allogenic haematopoietic cell transplantation, acute leukaemia or other haematologic diseases 144 treated with voriconazole and 133 treated with amphotericin B Herbrecht et al: NEJM 2002; 347: Which one is better? Voriconazole 6mg/kg bd on day 1 then 4mg/kg bd for 1 week then oral 200mg bd Amphotericin B deoxycholate (conventional) 1 to 1.5mg/kg At 12 weeks, voriconazole group vs amphotericin B group: Successful outcome: 52.8% vs 31.6% (95% CI difference 10.4 to 34.9) Survival rate: 70.8% vs 57.9% (95% CI hazard ratio 0.40 to 0.88) Which one is better? Caspofungin should not be used for primary therapy because of lack of data It can be used for those who cannot tolerate or refractory to primary therapy It can also be used in combination therapy Herbrecht et al: NEJM 2002; 347:

11 Combination therapy The role of combination antifungal therapy as either initial or salvage therapy is unproved since the benefit must be weighed against the increase in toxicity There are retrospective studies showing a marginal benefits of addition of caspofungin on top of amphotericin B therapy Aliff et al. Cancer 2003; 97: 1563 Kontoyiannis et al. Cancer 2003; 98:292 Combination therapy Data on combination of voriconazole and caspofungin seems more promising In one retrospective study of 47 patients with progressive aspergillosis despite amphotericin B therapy 31 received voriconazole only and 16 received voriconazole + caspofungin A significant lower rate of mortality (odds ratio 0.28) was found at 3 months Marr et al. Clin Infect Dis 2004; 39: 797 Combination therapy Another prosepective study involving 87 patients with SOT suffering from invasive aspergillosis 47 patients received lipid formulation of amphotericin B compared with 40 patients received caspofungin and voriconazole as primary therapy Survival rate at 90 days was better for those who received combination therapy (67.5% vs 51%) Current recommendation Decrease the degree of immunosuppression whenever possible Voriconazole as initial therapy Combination therapy for those who do not respond to initial therapy Duration of therapy is dependent upon the patient s s underlying disease and respond to therapy Singh et al. Transplantation 2006; Drug bill only counting antifungal Voriconazole 400mg bd = $1366 Total 9 months = $368,820 Caspofungin 70mg $4120 Total 8 weeks = $230,720 End Thank you Grand total = $599,540 (HKD) 11