Cryptococcus Meningitis – Making Amphotericin Float Like a Crashing Seagull and Sting Like a Scorpion

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Amphotericin B in the Brain, Punching Cryptococcus

Am I going there? Am I going to look into a topic that one of my attendings literally wrote the guidelines for? I guess I am. Cryptococcus is a yeast that is typically found everywhere there is bat/pigeon droppings or contaminated soil, as well as in certain tree species throughout the world. The most common species is C. neoformans, though the northwest has seen some cases of C. gattii. Regardless, if your immune system is ok, it really does not cause much problems. It is in immunocompromised patients, specifically those with HIV, where it can rear its ugly head in the form of meningoencephalitis, with some data to suggest this represents reactivation of a latent infection rather than new infection.  While ART has reduced the incidence of this disease, it is still fairly prevalent in third-world countries where they do not have access to many of the HIV medications as well as certain pockets of the US (looking at you, Grady and Amelia Court!). Here, I will limit to talking about induction therapy in AIDS patients; consolidation will be another topic. The name of the game is to clear the brain from the yeast as fast as possible and as safely as possible for maximum chances of success. Indeed, one retrospective analysis of 4 randomized trials found that the rate of CSF cryptococcal clearance was strongly associated with mortality in AIDS patients with meningitis(1):

Moreover, in both univariate and multivariate analysis, treatment that included amphotericin B was associated with a faster rate of clearance of infection. So amphotericin seems to be the backbone here.

Monotherapy 

Yeah, do not do this. Data for this usually comes from third-world countries, where toxicity of amphotericin B and lack of other therapeutics means they are very limited in terms of their tools. Despite this, it is helpful to put combination therapy into context and it may be useful for those who practice in resource-limited settings. While I will mention doses and length of induction therapy (which is what I will focus rather than maintennce therapy), I would not commit these to memory and instead, follow the guidelines. In one trial of HIV-positive patients, the early fungicidal activity  (EFA) of amphotericin B 1mg/kg/d was found to be superior to that of fluconazole 400mg/d during the first week of therapy (2). Early fungicidal activity was greater for those treated with amphotericin B (EFA -0.54 log CFU/mL of CSF) than fluconazole (-0.02 log CFU/mL of CSF). Further, mortality in the amphotericin B group was significantly lower than that in the fluconazole group, but the trial was fairly small to draw any conclusions and it seemed that those in the fluconazole cohort had more severe disease at the start. In a Ugandan trial of 58 patients, fluconazole monotherapy was compared to combination therapy with fluconazole and flucytosine (3). Fluconazole monotherapy consisted of 200mg daily for 2 months, while the combination therapy had the addition of 150mg/kg/d of flucytosine for 2 weeks. Combination therapy was associated with improved mortality at the end of the trial period, 36% in the monotherapy group compared to 56% in the combination cohort survived:

An open-label trial compared fluconazole monotherapy (1200mg/day) with the combination of high-dose fluconazole and flucytosine on the initial 2 week induction regimen (4). 41 patients were randomized, and the rate of fungal clearance was much faster in the combination cohort:

Furthermore, mortality was significantly lower at 2 and 10 weeks in the combination cohort (HR 0.24, 95% CI 0.05-1.16 for 2 weeks; HR 0.59, 95% CI 0.25-1.44 for 10 weeks):

So if high doses of fluconazole works, why not shoot for even higher? In a a trial of 81 patients, higher doses of fluconazole were associated with improved success as week 10, as well as the addition of flucytosine (5):

This, of course, only compares oral regimens rather than standard of care (i.e. amphotericin) so this is an option IF YOU CANNO DO AMPHOTERICIN B. Though with newer formulations, this may not be much of an issue (see later).

Combination Therapy: Amphotericin Deoxycholate + Flucytosine

So let’s throw amphotericin B into the mix. Recall, amphotericin B deoxycholate is the older, more toxic formulation of amphotericin B (in comparison to amphotericin B lipid complex aka ABLC or liposomal amphotericin B aka L-AmB, which are carried by lipid vehicles to avoid nephrotoxicity) so many of the early trials have this caveat to them. One of the oldest trials came in 1979, which compared 6 weeks of amphotericin B (0.3mg/kg/d) + flucytosine compared to 10 weeks of amphotericin B alone (0.4mg/kg/d for the first 42 days -> 0.8mg/kg/d for the last 28 days, 6). 78 patients were enrolled, and at the end of the trial 66% of patients in the combination were cured or improved, compared to 47% in the amphotericin B group alone (p >0.05). Moreover, the combination group tended to have faster CSF culture conversion than the monotherapy group:

In a much later trial, amphotericin B (0.7mg/kg/d) was compared with either flucytosine (100mg/d) or placebo for induction therapy (7). At the two week period, 60% of patients in the combination group achieved CSF culture negativity compared to 51% of those who got amphotericin B alone (p=0.06). There was no difference in clinical outcomes or mini-mental status exam:

A relatively more recent trial of 208 patients with cryptococcosis (8), combination therapy with amphotericin B and flucytosine  was associated with a lower likelihood of mycological failure at 2 weeks when compared to monotherapy (23% for combination vs 47% for monotherapy, p <0.001). Further, combination therapy was associated with lower treatment failure rates in those with meningoencephalitis (25% vs 72%, p <0.001). Multivariate analysis found that lack of induction therapy with 5-FC and AMB was associated with treatment failure at 2 weeks (OR 51.25, 95% CI 9.67 to 271.52). 

As you have no doubt seen, the above trials used a “modest” dose ranging from 0.3mg/kg/day to 0.7mg/kg/day. What if we can shoot for higher doses to improve rate of CSF sterilization? A randomized trial compared standard doses of AmB (0.7mg/kg/d) with higher dose of 1mg/kg/d in combination with flucytosine for induction to compare the rate of cryptococcal sterilization (9). 64 patients were enrolled, with the rate of clearance being faster in the higher dose group (-0.56 +/- 0.24 vs -0.45 +/- 0.16 log CFU/mL per day). Notably, mortality was not statistically different at 2 or 10 weeks between both groups. More patients in the higher dose group had a creatinine >2x their baseline at the end, as well as had a drop in hemoglobin when compared to standard dose, though only 5 patients in the higher dose group discontinued therapy compared to one in the lower dose group. So no change in mortality as far as this one goes, but it seems in general, patients may be able to tolerate higher AmB doses. What if you adjust the duration? A 1997 trial (10) of 91 patients evaluated amphotericin B (0.3mg/kg/d)+ flucytosine (150mg/kg/d) for four weeks vs six weeks. The 4 week regimen was associated with improvement/cure in 75% of patients compared to 85% in the 6 week regimen, which is fairly comparable. Relapse rates, however, were higher in the 4 week cohort (27%) than in the 6 week cohort (16%).  

This is to show 2 things:

  1. Clearance of CSF is achieved faster with amphotericin
  2. Combination with flucytosine seems to be the go-to (see in a bit)
  3. Patients may be able to tolerate higher doses of AmB for a shorter time. 

Combination Therapy: Enter Fluconazole

The data here is a bit mixed, especially early on, but as you will see the addition of PO fluconazole either as monotherapy or in combination when you have additional antifungals may not provide much benefit. A randomized trial evaluated fluconazole 400mg/day vs amphotericin B plus flucytosine in a 2:1 fashion (11). The fluconazole group were given 400mg/day for 10 weeks followed by 200mg per day for maintenance, while the amphotericin B group were dose at 0.7mg/kg/d for the first week, followed by 0.7mg/kg three times per week for 9 weeks. More patients with AIDS in the fluconazole group failed therapy when compared to the amphotericin B arm (57% vs 0%, p=0.05). Moreover, positive CSF fluid culture time was significantly shorter in the amphotericin B cohort (40.6 +/- 5.4 days in the fluconazole cohort vs 15.6 +/- 6.6 days in the amphotericin B cohort). Two other cohorts evaluated fluconazole with certain combinations. In one cohort (12), fluconazole 400mg per day was combined with flucytosine 150mg/kg/day for 10 weeks. 49 patients were enrolled with 63% achieving clinical success at week 10. In a trial of 64 patients, treatment with amphotericin B alone was as effective as dual therapy with either amphotericin B + flucytosine, amphotericin B + fluconazole, or triple therapy (13). Notably, amphotericin B + flucytosine was found to have higher early fungicidal activity when compared to other types of therapy. These latter findings were further coroborated in a larger trial, non-inferiority trial compared the standard 2 week amphotericin B (1mg/kg/day) + flucytosine regimen, high dose oral fluconazole (1200mg per day) + flucytosine, and amphotericin B + fluconazole/flucytosine for one week (14). Mortality at 2 weeks, 4 weeks, 10 weeks and fungicidal activity was not different between groups:

Notably, the combination of amphotericin B + flucytosine was superior to amphotericin B + fluconazole in terms of 10-week mortality (HR 0.62, 95% CI 0.45 to 0.84). Moreover, the 1-week amphotericin B induction regimen had a lower 10-week mortality than the 2 week amphotericin B regimen (aHR 0.59, 95% CI 0.36 to 0.96). 

So fluconazole may be good for consolidation therapy rather than induction (topic for another post), however it seems the combination of amphotericin B and flucytosine is the go to. Indeed, this last trial actually evaluates the standard therapy, which is AmB + flucytosine for 2 weeks. 

What About Amphoterrible?

Despite the trials including mostly amphotericin deoxycholate, it seems that the other formulations of amphotericin may be as effective as conventional formulations.  One trial compared escalating doses of amphotericin B lipid complex (ABLC) to standard of amphotericin B deoxycholate in HIV patients for 6 weeks as shown below (15):

55 patients were enrolled, with the clinical response in the ITT analysis being 86% in cohort III the ABLC recipients vs 65% in the AmB. In terms of adverse events (the real point of this study), 24% of patients discontinued ABLC compared to 53% in the AmB group, with escalating doses of ABLC leading to higher change in creatinine from baseline:

This is more of a proof-of-concept trial, where the safer formulation of amphotericin B could be used for cryptococcal meningitis. One open-label randomized trial evaluated liposomal amphotericin B 4mg/kg with amphotericin B deoxycholate (0.7mg/kg) for 3 weeks of induction therapy, followed by consolidative fluconazole (16). 28 patients were randomized, with fairly equivalent clinical response rates after the first 3 weeks (80% for LAmB vs 86% in the Amphotericin B deoxycholate). The results were similar in the 10 week mark (87% in the LAmB vs 83% in AMB). While the clinical results were otherwise similar, those in the LAmB group tended to achieve negative CSF culture conversion at the end of 3 weeks:

While side effect numbers were similar between the two, there were notably less symptomatic adverse events or lab-related one in the LAmB arm. Moreover, this only included induction monotherapy sans flucytosine, however it shows that L-AmB may be as effective, or more, as conventional amphotericin B.  The most robust data comes from a 2010 trial, where 2 doses of L-AmB were compared to conventional amphotericin B (17). Patients were randomized in a 1:1:1 fashion to either amphotericin B 0.7mg/kg/d, L-AmB 3mg/kg/d, or L-AmB 6mg/kg for induction period target of 14 days without concomitant flucytosine. After induction, all patients received 400mg of fluconazole for 10 weeks daily. 267 patients were included in the ITT population, with all 3 groups being fairly balanced with the exception of L-AmB 6mg/kg which had a significantly higher mean CSF cryptococcal antigen than the other 2 groups.  At week 2, there were no differences in mycological success between groups, nor was there a difference at week 10:

Similarly, clinical success was not statistically different between the groups, suggesting that the liposomal amphotericin formulation is as effective as conventional amphotericin B. Notably, however, there were more infusion related adverse events in the conventional group when compared to the liposomal cohorts:

Renal function was also worse in the conventional cohort:

Overall, this suggests that these 2 doses are at least as effective as conventional amphotericin, though this trial was without flucytosine. 

Other combinations have been tried. For instance, one trial (18) evaluated 4 regimens (amphotericin B + flucytosine for 2 weeks; AmB + fluconazole 800mg for 2 weeks, amphotericin B + fluconazole 600mg BID for 2 weeks, amphotericin B + voriconazole 300mg daily for weeks) to compare rate of CSF early fungicidal activity. Doses of AmB were 0.7mg/kg/d or 1mg/kg/d with adjustments as necessary. 80 patients were enrolled, with no statistical difference in rate of clearance of cryptococcal CFU:

Mortality by 10 weeks was also similar among all groups (around 25-30%).

TL;DR

  • With cyrptococcal meningitis in AIDS patients, name of the game is to clear the CSF as quickly and as safely as you can
  • Amphotericin B is the backbone of therapy here
  • Combination of agents is superior to monotherapy
  • Specifically: amphotericin B + flucytosine
  • Guidelines favor conventional amphotericin (19) given the propensity of data, but other formulations seem to work well though this has not bee compared in proper trials where the combinations (i.e. flucytosone + AmB vs flucytosine vs L-AmB) have been compared 

References:

  1. Bicanic T, Muzoora C, Brouwer AE, Meintjes G, Longley N, Taseera K, Rebe K, Loyse A, Jarvis J, Bekker LG, Wood R, Limmathurotsakul D, Chierakul W, Stepniewska K, White NJ, Jaffar S, Harrison TS. Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients. Clin Infect Dis. 2009 Sep 1;49(5):702-9. doi: 10.1086/604716. PMID: 19613840; PMCID: PMC2965403.
  2. Bicanic T, Meintjes G, Wood R, Hayes M, Rebe K, Bekker LG, Harrison T. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis. 2007 Jul 1;45(1):76-80. doi: 10.1086/518607. Epub 2007 May 25. Erratum in: Clin Infect Dis. 2007 Aug 15;45(4):526. PMID: 17554704.
  3. Mayanja-Kizza H, Oishi K, Mitarai S, Yamashita H, Nalongo K, Watanabe K, Izumi T, Ococi-Jungala, Augustine K, Mugerwa R, Nagatake T, Matsumoto K. Combination therapy with fluconazole and flucytosine for cryptococcal meningitis in Ugandan patients with AIDS. Clin Infect Dis. 1998 Jun;26(6):1362-6. doi: 10.1086/516372. PMID: 9636863.
  4. Nussbaum JC, Jackson A, Namarika D, Phulusa J, Kenala J, Kanyemba C, Jarvis JN, Jaffar S, Hosseinipour MC, Kamwendo D, van der Horst CM, Harrison TS. Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi. Clin Infect Dis. 2010 Feb 1;50(3):338-44. doi: 10.1086/649861. PMID: 20038244; PMCID: PMC2805957.
  5. Milefchik E, Leal MA, Haubrich R, Bozzette SA, Tilles JG, Leedom JM, McCutchan JA, Larsen RA. Fluconazole alone or combined with flucytosine for the treatment of AIDS-associated cryptococcal meningitis. Med Mycol. 2008 Jun;46(4):393-5. doi: 10.1080/13693780701851695. PMID: 18415850.
  6. Bennett JE, Dismukes WE, Duma RJ, Medoff G, Sande MA, Gallis H, Leonard J, Fields BT, Bradshaw M, Haywood H, McGee ZA, Cate TR, Cobbs CG, Warner JF, Alling DW. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis. N Engl J Med. 1979 Jul 19;301(3):126-31. doi: 10.1056/NEJM197907193010303. PMID: 449951.
  7. van der Horst CM, Saag MS, Cloud GA, Hamill RJ, Graybill JR, Sobel JD, Johnson PC, Tuazon CU, Kerkering T, Moskovitz BL, Powderly WG, Dismukes WE. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med. 1997 Jul 3;337(1):15-21. doi: 10.1056/NEJM199707033370103. PMID: 9203426.
  8. Dromer F, Bernede-Bauduin C, Guillemot D, Lortholary O; French Cryptococcosis Study Group. Major role for amphotericin B-flucytosine combination in severe cryptococcosis. PLoS One. 2008 Aug 6;3(8):e2870. doi: 10.1371/journal.pone.0002870. PMID: 18682846; PMCID: PMC2483933.
  9. Bicanic T, Wood R, Meintjes G, Rebe K, Brouwer A, Loyse A, Bekker LG, Jaffar S, Harrison T. High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial. Clin Infect Dis. 2008 Jul 1;47(1):123-30. doi: 10.1086/588792. PMID: 18505387.
  10. Dismukes WE, Cloud G, Gallis HA, Kerkering TM, Medoff G, Craven PC, Kaplowitz LG, Fisher JF, Gregg CR, Bowles CA, Shadomy S, Stamm AM, Diasio RB, Kaufman L, Soong S, Blackwelder WC; National Institute of Allergy and Infectious Diseases Mycoses Study Group. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. N Engl J Med. 1987 Aug 6;317(6):334-41. doi: 10.1056/NEJM198708063170602. PMID: 3299095.
  11. Larsen RA, Leal MA, Chan LS. Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS. A randomized trial. Ann Intern Med. 1990 Aug 1;113(3):183-7. doi: 10.7326/0003-4819-113-3-183. PMID: 2197908.
  12. Larsen RA, Bozzette SA, Jones BE, Haghighat D, Leal MA, Forthal D, Bauer M, Tilles JG, McCutchan JA, Leedom JM. Fluconazole combined with flucytosine for treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis. 1994 Oct;19(4):741-5. doi: 10.1093/clinids/19.4.741. PMID: 7803641.
  13. Brouwer AE, Rajanuwong A, Chierakul W, Griffin GE, Larsen RA, White NJ, Harrison TS. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet. 2004 May 29;363(9423):1764-7. doi: 10.1016/S0140-6736(04)16301-0. PMID: 15172774.
  14. Day JN, Chau TTH, Wolbers M, Mai PP, Dung NT, Mai NH, Phu NH, Nghia HD, Phong ND, Thai CQ, Thai LH, Chuong LV, Sinh DX, Duong VA, Hoang TN, Diep PT, Campbell JI, Sieu TPM, Baker SG, Chau NVV, Hien TT, Lalloo DG, Farrar JJ. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013 Apr 4;368(14):1291-1302. doi: 10.1056/NEJMoa1110404. PMID: 23550668; PMCID: PMC3978204.
  15. Sharkey PK, Graybill JR, Johnson ES, Hausrath SG, Pollard RB, Kolokathis A, Mildvan D, Fan-Havard P, Eng RH, Patterson TF, Pottage JC Jr, Simberkoff MS, Wolf J, Meyer RD, Gupta R, Lee LW, Gordon DS. Amphotericin B lipid complex compared with amphotericin B in the treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis. 1996 Feb;22(2):315-21. PMID: 8838189.
  16. Leenders AC, Reiss P, Portegies P, Clezy K, Hop WC, Hoy J, Borleffs JC, Allworth T, Kauffmann RH, Jones P, Kroon FP, Verbrugh HA, de Marie S. Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS. 1997 Oct;11(12):1463-71. doi: 10.1097/00002030-199712000-00010. PMID: 9342068.
  17. Hamill RJ, Sobel JD, El-Sadr W, Johnson PC, Graybill JR, Javaly K, Barker DE. Comparison of 2 doses of liposomal amphotericin B and conventional amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis: a randomized, double-blind clinical trial of efficacy and safety. Clin Infect Dis. 2010 Jul 15;51(2):225-32. doi: 10.1086/653606. PMID: 20536366.
  18. Loyse A, Wilson D, Meintjes G, Jarvis JN, Bicanic T, Bishop L, Rebe K, Williams A, Jaffar S, Bekker LG, Wood R, Harrison TS. Comparison of the early fungicidal activity of high-dose fluconazole, voriconazole, and flucytosine as second-line drugs given in combination with amphotericin B for the treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis. 2012 Jan 1;54(1):121-8. doi: 10.1093/cid/cir745. Epub 2011 Nov 3. PMID: 22052885.
  19. John R. Perfect, William E. Dismukes, Francoise Dromer, David L. Goldman, John R. Graybill, Richard J. Hamill, Thomas S. Harrison, Robert A. Larsen, Olivier Lortholary, Minh-Hong Nguyen, Peter G. Pappas, William G. Powderly, Nina Singh, Jack D. Sobel, Tania C. Sorrell, Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America, Clinical Infectious Diseases, Volume 50, Issue 3, 1 February 2010, Pages 291–322, https://doi.org/10.1086/649858

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