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Antifungal Treatment for Cryptococcal Meningitis

Antifungal Treatment for Cryptococcal Meningitis. Li-Ping Zhu, Xin-Hua Weng Huashan Hospital, Fudan University Shanghai China. Challenge for Cryptococcal Meningitis. Cryptococcus neoformans is the most common cause of fungal meningitis in HIV and non-HIV-infected patients

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Antifungal Treatment for Cryptococcal Meningitis

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  1. Antifungal Treatment for Cryptococcal Meningitis Li-Ping Zhu, Xin-Hua Weng Huashan Hospital, Fudan University Shanghai China

  2. Challenge for Cryptococcal Meningitis • Cryptococcus neoformans is the most common cause of fungal meningitis in HIV and non-HIV-infected patients • Found in 7%-10% patients with AIDS • Remain high mortality rate (10%-44%), especially in immunocompromised patients

  3. Case Study

  4. Present History • A 46-year-old man was admitted to our hospital because of fevers and headache for over 2 months • Lumbar puncture showed a WBC count of 58×106/L with 0.94 monocytes, protein was 176mg/dL, and glucose was 1.5mmol/L • Failed for treating with broad spectrum antibiotics including ceftazidime, levofloxacin, etc. • His temperature continued to climb up to 39˚C, and his headache developed into an intolerable one. He was then transferred to our hospital

  5. Lab Examinations • CSF: WBC28×106/L，multinucleated cells 15/28，monocytes 13/28，protein 1169mg/L，glucose1.3mmol/L • CSF smear for fungi was negative • CSF culture was positive for Cryptococcus neoformans • CSF cryptococcal antigen titres 1:160

  6. Cranial MRI

  7. Past History of Hepatitis B • In 2002 he was diagnosed with decompensated hepatitis B cirrhosis, presenting with fatigue, anorexia and bloating • HBVM: HBsAg(+), HBeAg(+), HBcAB(+) • HBV DNA was 2.2×107 copies/mL

  8. Past History of Hepatitis B • He took Lamivudine 100mg/d，and witnessed a reduction of viral load to 3.8×103 copies/mL. 15 months later he developed YMDD mutation and viral load rebounded to 1.0×107copies/mL • Since then he had several episodes of jaundice, liver enzyme elevation, ascites and spontaneous bacterial peritonitis. Symptoms were relieved each time after anti-infective and supportive therapy • HBV DNA was 6.19×108 copies/mL in July 2005. Adefovir 10mg/d was added to lamivudine

  9. Liver CT

  10. How can I initially treat this patient? • AmB • L-AmB • Fluconazole • Itraconazole • Posaconazole • Flucytosine

  11. Roadmap • Clinical studies in the pre-HIV Era • Clinical studies in the AIDS Era • Recent studies for cryptococcal meningitis

  12. Clinical studies in the pre-HIV Era

  13. AmB • Prior to the availability of AmB, cryptococcal meningitis was considered to be uniformly fatal • When AmB became available in the late 1950s, it became the drug of choice for crypotococcal meningitis with success rates of up to 60% • Successful therapy was often limited by severe nephrotoxicity, electrolyte abnormalities, and infusion-related adverse events

  14. Landmark therapy • Two major randomized clinical trials addressing the treatment of cryptococcal meningitis were conducted in the late 1970s and mid- 1980s • Establishing the “gold standard” to which every subsequent regimen has been compared

  15. The first milestone clinical trial • AmB (0.4 mg/kg.d) vs. AmB (0.3 mg/kg.d) and 5-FC • 27 treated with AmB alone for 10wks 24 with a combination of AmB and 5-FC for only 6wks • Combination more effective Cure/improved (66% vs 41%) Relapses (5% vs 18%) Sterilization of CSF: rapid Nephrotoxicity: decreased --Bennett et al. N Engl J Med. 1979. 301: 126

  16. The second large randomized trial • AmB (0.3mg/kg.d) + 5-FC for 4 vs. 6wks • 91 patients met criteria for randomization to either discontinuing therapy at 4 wks. or continuing therapy for 2 additional wks • Better efficacy for 6wks. Cure/improved: higher 6 wks. (85% vs. 75%) Relapses: lower for 6 wks. (16% vs. 27%) --Dismukes et al. N Engl J Med. 1987. 317:334

  17. Clinical studies in the AIDS Era

  18. The first large randomized trial • AmB (0.4-0.5 mg/kg.d) vs. Fluconazole(400 mg/d) for 10 weeks • Better efficacy for AmB Success (40% vs. 34%) and overall mortality rate same (14% vs. 18%) Higher mortality rate at 2 wks in Fluconazole patients (15% vs. 8%) More rapid sterilization of CSF in the AmB recipients --Saag et al. N Engl J Med. 1992. 326: 83

  19. The second randomized, double-blinded study • AmB (0.7mg/kg.d) ± 5-FC (100mg/kg.d) for 2 wks followed by fluconazole (400mg/kg) or itraconazole (400mg/d) for 8 wks. • 381 patients received AmB 0.7 mg/kg/d for the first 2 weeks plus either 5-FC 100 mg/kg/d (202 patients) or placebo (179 patients) • At 2 wks, mortality 5.5% • At 10 wks, mortality 3.9% (no difference) and rapid sterilization of CSF with fluconazole --Van der Horst et al. N Engl J Med. 1997. 337: 15

  20. Maintenance therapy in AIDSpatient • AmB (1.0mg/kg.wk) vs. fluconazole (200mg/d) for 12 mos. Relapse rate 19% vs. 2% Serious drug-related events more frequent in AmB patients --Powderly et al. N Engl J Med. 1992.326:793 • Fluconazole (200mg/d) vs. itraconazole (200mg/d) for 12 mos. Relapse rate 4% vs. 23% --Saag et al. Clin Infect Dis.1999. 28: 297

  21. The treatment of cryptococcal meningitis in patients with AIDS • Induction AmB + 5-FC for two wks. • Consolidation High dose fluconazole (400 mg/d for normal hepatic and renal function) can be initiated • Maintenance At the completion of 8 weeks, fluconazole (200 mg/d) can be continued for long-term chronic suppression

  22. The treatment of cryptococcal meningitis in HIV-negative patients

  23. Recent studies

  24. Update on maintenance If the patient has an excellent response to HAART, then discontinuation of maintenance therapy can be considered • Asymptomatic • Responding to HAART with a sustained increase in their CD4+ T lymphocytes for more than a year to greater than 100 cells/µL (and greater than 10 percent CD4) • These patients should be monitored closely, and fluconazole maintenance reinstituted if the CD4 count falls below 100 cells/µL (and below 10 percent CD4 cells) Mussini et al. Clin Infect Dis. 2004. 38: 565

  25. Cryptococcal IRIS in AIDS patients • Treatment with HAART during antifungal therapy can cause cryptococcal IRIS (Immune Reconstitution Inflammatory Syndrome) Increased CSF OP, increased CSF glucose levels and WBC • antiretroviral drug-naïve patients • HAART in close proximity to OI diagnosis • Rapid decline in HIV RNA levels --Shelburne et al. Clin Infect Dis. 2005. 40: 1049. --Shelburne et al. AIDS. 2005. 19 : 399.

  26. Cryptococcal IRIS in AIDS patients • 30% of patients with cryptococcosis have IRIS • IRIS commonly occurs within the first 1 to 2 months after starting HAART • After starting antifungal therapy for cryptococcal diseases, an 8- to 10-week delay in initiating HAART is generally recommended to reduce the complexities of dealing with IRIS --Shelburne et al. Clin Infect Dis. 2005. 40: 1049

  27. Cryptococcosis/Immune Syndrome Inflammatory Reconstitution/Organ Transplant • IRIS 5.5% (3/54) • Worsening symptoms despite negative cultures • Etiology: effective antifungal treatment and/or cessation of immunosuppresive therapy (tacrolimus, mycophenolate, prednisone) • Temporal association of graft loss Singh et al Clin Infect Dis. 2005. 40: 1756 Singh et al Transplantation. 2005. 80: 1131

  28. Fluconazole as first-line therapy? • In a South African trial, 27 patients with cryptococcal meningitis were treated with fluconazole as first-line therapy • Two-thirds of the patients had a clinical relapse associated with positive cultures • The majority of these isolates had reduced susceptibility to fluconazole • Despite the subsequent administration of AmB therapy, mortality was high

  29. Retrospective study in non-AIDS patients • 306 non-HIV-infected patiens with cryptococcosis, among whom 157 patients had CNS disease • 90% of patients receiving an AmB-containing regimen as initial therpay • The median duration of therapy with AmB was 27 days in this population, and about two thirds also received 5-FC for a median time of 31 days • The total amount of AmB given as antifungal therapy was approximately 800 mg, and the total daily dose of 5-FC was approximately 100 mg/kg • Fluconazole was given as initial therapy at doses of 400 to 800 mg in only a few patients • Fluconazole was given in two thirds of patients following a successful induction regimen containing AmB • These patients received fluconazole at a median dose of 400 mg for a median duration of 10 weeks • Other initial regimens were uncommon and could not be adequately assessed Pappas et al. Clin Infect Dis. 2001. 33: 690

  30. AmB lipid formulations • Liposomal AmB the same effective as AmB • Less toxic than AmB • CSF culture conversion significantly earlier than did patients given AmB --Leenders et al. AIDS. 1997. 11: 1463 --Hamill et al. 1999. 39th ICAAC, San Francisco, Abstract 1161

  31. AmB lipid complex • The use of AmB lipid complex has been studied in both HIV-positive and –negative patients with CNS cryptococcosis --Sharkey et al. Clin Infect Dis. 1996. 22:315 --Baddour et al. Clin Infect Dis. 2005. 40: S409 • Compared with AmB, AmB lipid complex produces higher clinical response rates (86% vs. 65%) and less toxicity --Sharkey et al. Clin Infect Dis. 1996. 22:315

  32. Collaborative Exchange of Antifungal Research (CLEAR) study • 83 patients with CNS cryptococcosis • 65% for those with CNS disease • 56% for those whose disease was refractory to prior antifungal therapy --Baddour et al. Clin Infect. Dis. 2005. 40: S409

  33. Lipid formulations of AmB to be effective and less toxic • To be particularly useful for patients developing significant infusional toxicities or renal failure on conventional AmB therapy

  34. Other new antifungal drugs Voriconazole • 18 patients with both cryptococcal meningitis and AIDS • Response rate 39%（7/18） • 10 out of the 11 patients that did not respond were stable • Survival rate at 3 months >90% --Perfect et al. Clin Infect Dis. 2003. 36: 1122

  35. Posaconazole • An open-label international multicenter clinical trial • 29 patients with cryptococcal meningitis received posaconazole oral suspension （800mg/d） • Most patients were refractory to prior therapy of conventional AmB, AmB lipid formulations or fluconazole therapy • Response rate 48%（14/29） • May be suitable as consolidation or maintenance therapy for cryptococcal meningitis --Pitisuttithum et al. J Aantimicrob Chemother. 2005. 56: 745

  36. Role of Combination Therapy • Randomized controlled trial of initial combination antifungal therapies for treatment of cryptococcal meningitis • 64 patients enrolled (2-3 per week) • 4 arms: initial 2 weeks: AmB alone (0.7 mg/kg/d) AmB + 5-FC (100 mg/kg/d) AmB + fluconazole (400 mg/d) AmB + 5-FC + fluconazole • Fluconazole 400mg/d 8weeks • Fluconazole 200 mg/d thereafter Brouwer et al. Lancet. 2004. 363:1764

  37. Results • All treatments well-tolerated no drug discontinuation in first 2 weeks • Overall mortality 2 weeks - 14% 10 weeks - 22% • The most rapidly fungicidal regimen AmB + 5-FC • Recommendations for induction therapy AmB + 5-FC

  38. Case Study for Treatment Schedule • Induction Intravenous itraconazole 200mg/d for 21d. Body temperature returned normal, headache disappeared • Consolidation Intravenous fluconazole 200mg/d for 10w. CSF cytology and chemistry turned normal • Maintenance oral fluconazole 200mg/d • The patient had kept afebrile and symptom-free thereafter

  39. Changing of the Temperature

  40. Cranial MRI (after treatment)

  41. Liver function test 10 months follow-up after discontinuation • ALT 23 U/L • TB 74 µ mol/L • DB 20.8 µ mol/L • A/G 26/ 46 g/L • HBV DNA (-)

  42. Conclusion • AmB-based therapy remains the gold standard • AmB + 5-FC: more effective and more rapid clearance of the fungus from CSF • Adherence to the guideline has been shown to generally improve outcome • Specific clinical situations may dictate creative management plans

  43. Thanks for your attention!

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