Bad Bug, Bad Bug – Or Mould? Meet Your Demise

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Last week I talked about invasive pulmonary aspergillosis in influenza and COVID patients. This is not the first time I have talked about this topic. I have mentioned how the halo sign is not terribly specific for IPA, especially in hematological patients and the testing characteristics of galactomannan. I have also spoken about the other family of invasive moulds. Given this, I think it is reasonable to turn our attention into the treatment options for invasive pulmonary aspergillosis.

The CliffsNotes for this post is as follows:

  • Voriconazole is the first line therapy for suspected aspergillous infection
  • Liposomal Amphotericin B is another option with its niche being salvage therapy, though there is some resistance to A. terrus, and it seems that higher dosing is just as good as standard dosing
  • Isavuconazole is a reasonable alternative, as is posaconazole, though there is no high quality data here
  • There may be a benefit to dual therapy with a mould active triazole + echinocandin in patients with IPA and positive serum galactomannan. Data supports the use of voriconazole rather than posa or isavuconazole, but suspect all could be used in its place.

Efficacy of current antifungals on Aspergillus spp

If there is a good (at least as  of the time writing this) summary of MICs for each antifungal and mould combination, it would be this evaluation of susceptibility testing of 448 samples (1):

A few things to note here:

  • A. fumigatus is fairly susceptible to most antifungals (lets ignore itraconazole)
  • Amphotericin does poorly with A. terreus
  • Posaconazole and voriconazole do fairly well with most samples (at least in this study, given it is relatively old, your mileage may vary).

Triazoles

Given the fairly good susceptibility profile of voriconazole in comparison to amphotericin B (see a prior post), the former has emerged as the preferred first-line therapy. An open label, RCT compared voriconazole and amphotericin B deoxycolate (i.e. the worst type of amphotericin B) in immunocompromised patients with pulmonary aspergillosis. Primary outcome was non-inferiority in the ITT population at 12 weeks. Patients in the voriconazole group were more likely to have a successful outcome in the mITT group (52.8% vs 31.6%) when compared to the amphotericin B group.

Mortality was also significantly better in the voriconazole group, 70.8% vs 57.9% at 12 weeks:

A re-analysis of this study (3) using the 2008 EORTC/MSG criteria to re-classify some of the cases used in this study also found that patients started on voriconazole had a higher rate of favorable response when compared to AmB (54.7% vs 29.9%, p-value <0.0001). A larger proportion of patients in the voriconazole group had better survival at week 12 when compared to AmB in A) all patients with IPA B) probable and proven IPA C) possible IPA and D) HSCT patients with IPA:

Whether or not this difference was marked by the discontinuation of amphotericin B given the higher likelihood of renal impairment is unclear, but likely played a role. While not LAmB, it is likely that LAmB would have a higher incidence of renal injury when compared to voriconazole regardless.

A retrospective study specifically looking at A. terrus infection in immunocompromised patients (4) compared outcomes at week 12 between voriconazole and other antifungals (including amphotericin B, caspofungin, and other azoles). 83 patients were evaluated, and those who received voriconazole during their stay had lower mortality overall (55.8%) when compared to the other antifungal group (73.4%). When evaluating the patients who started on voriconazole, their survival rate was higher than those who got it as second or third line therapy (64.7% vs 23.5%, p-value 0.04). Survival rate in those who got amphotericin B as first line therapy was 26.2%, p-value 0.01). In bivariate analysis, treatment with voriconazole was associated with improve outcomes, which held true in multivariate analysis:

How much Voriconazole do you need? Do you need to measure the levels of voriconazole? A single center study (5) evaluated patients with invasive fungal infections in which voriconazole levels were measured. 52 patients had measured levels. Among patients who had a voriconazole trough >1mg/L, patients had a higher treatment success than those with a trough <1mg/L.

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Notably, those patients with voriconazole levels >5.5mg/L had higher levels of adverse events, including higher rates of encephalopathy (31% vs 0%) and cholestatic hepatopathy (19% vs 8%).

Recently, Isavuconazole has emerged as a possible alternative to voriconazole for primary therapy. One of the advantages of this drug is the QTc shortening and a better side effect profile. A non-inferiority double blind, RCT compared isavuconazole to voriconazole (6) in patients with suspected invasive mold disease. Patients were randomized in a 1:1 fashion. Primary endpoint was all-cause mortality at day 42. Overall, 19% of patients in the isavuconazole group vs 20% of patients in the voriconazole group archived the primary endpoint (95% CI -7.8 to 5.7).

Further, isavuconzaole had lower frequency of hepatobiliary disorders as well as visual disturbances and skin disorders and patients in the isavuconzoale group were less likely to discontinue the medication (14% vs 23%).

Another reasonable option here is posaconazole. While data is sparse, an in vitro alveolus model and animal model (7) was able to show that posaconazole was able to suppress galactomannan expression in susceptible strains of Aspergillus. An externally-controlled multicenter study (8) evaluated the use of posaconazole as salvage therapy, with 107 patients in the posaconazole group being compared to 86 in the control group. At the end of therapy, more patients in the posaconazole group had complete and partial response (42%) compared to the control group (26%, OR by adjusted logistic regression model 4.06, 95% CI 1.50-11.04). Posaconazole treated patients tended to fare well despite their neutropenia status:

And it seemed to confer a survival benefit when compared to the salvage control group:

In general, delayed release posaconazole tablets tend to have higher bioavailability than suspension. A report (9) evaluated 12 patients who were using posaconazole suspension who were subsequently transitioned to tablets. Patients were found to have higher median concentrations when using tablets (1910 ng/mL) when compared to the suspension period (748ng/mL, p <0.01). While specific data for posaconazole as primary therapy is not readily available, it seems reasonable to use if there are any concerns with the other triazoles.

Liposomal Amphotericin B

While voriconazole and Isavuconazole have emerged as viable first line therapies for pulmonary aspergillosis, liposomal amphotericin B is still a viable option for therapy. Higher doses of liposomal amphotericin do not seem to be of benefit here. In a randomized, double blind trial comparing 10mg/kg of liposomal amphotericin B and 3mg/kg (10), 50% of patients in the 3mg/kg group achieved a favorable outcome compared to 46% in the 10mg/kg group, suggesting no difference between doses. Further, at 12 weeks, there was no differences in survival between groups:

Notably, more patients in the high dose group had a higher rate of adverse events, including hypokalemia and increase in creatinine. In general, using 5mg/kg for liposomal amphotericin B is a reasonable approach, with stepdown to either voriconazole or posaconazole after about 1-2 weeks is reasonable. The total duration here is difficult to determine, but roughly 12 weeks or until clinical resolution is standard practice, though there is little data to go off of here. In general, for Aspergillosis LAmB would be more of a salvage therapy.

Combination Therapy

This has been gaining traction in case studies over the past few years. The idea behind combination is syngergy and the potential to broaden the spectrum to avoid resistant pathogens (11). A remote review evaluated several drug combinations for Aspergillus spp (11):

Early data came from cohort studies. A retrospective analysis of patients treated with caspofungin + either azoles or amphotericin B (12) who were refractory to initial therapy found a rate of success of 55% at the end of therapy, and a mortality of 45% at day 84 of the study. Further, 32% of patients experienced a clinical adverse event. Another retrospective cohort study of 101 patients who received the combination of caspofungin and LAmB (13) found the combination to be more successful as primary therapy rather than for salvage therapy though this did not reach statistical significance (53% vs 35%, p-value 0.365).  An analysis of 47 patients (14) evaluated the combination of caspofungin with voriconazole as salvage therapy and found a significant mortality benefit for the combination group compared to the voriconazole only group:

A larger, prospective multicenter observational study (15) evaluated this combination in a group of solid organ transplant recipients as primary therapy in IPA. Primary endpoint was survival at 90 days. The group included 40 cases who received the combination therapy and 47 who received LAmB. Overall survival in the combination group at 90 days was 67.5% (27/40) compared to 51% of the LAmB group (24/47, HR 0.57, 95% CI 0.29-1.1, p-value 0.11):

In subgroup analysis, the combination therapy was associated with reduced mortality in those with renal failure (HR 0.39, 95% CI 0.16-0.96) and in those with A. fumigatus infection (HR 0.41, 95% CI 0.18-0.92), though the former may have been due to the more kidney friendly combination.

The largest randomized trial involved 454 patients in patients with HSCT or hematological malignancies and suspected or documented invasive pulmonary aspergillosis (16). Patients were allocated in a 1:1 fashion to receive voriconazole plus either anidulafungin or placebo for a minimum of 2 weeks with voriconazole monotherapy continued for a total of 6 weeks. Primary end point was all-cause mortality at 6 weeks. In the mITT population, the 6 week mortality was 27.8% in the monotherapy group vs 19.5% in the combination group (treatment difference -8.3, 95% CI -19 to 1.5).

A post-hoc analysis of mortality in the positive galactomannan group found that all-cause mortality was 15.7% (17/108) in the combination group compared to 27.3% (30/110), which achieved statistical significance (difference -11.6, CI -22.7 to -0.4, p-value 0.037):

Notably, there was a trend towards overall mortality in the combination group which reached statistical significance in those who have positive galactomannan (and as such, more severe disease). It may be reasonable to use combination antifungal therapy voriconazole and an echinocandin, while reserving amphotericin B as salvage therapy.

The data for other triazoles is sparse. Isavuconazole and micafungin was used in an experimental model of IPA in neutropenic rabbits (17). Patients in the combination group had lower pulmonary infarct scores and lower decreased lung weight:

Further rabbits in the combination group were more likely to survive and have lower fungal burden:

At the end of the day, there is only one well designed study to support the use of voriconazole and echinocandins. The use of other triazoles has not been studied, and there is less enthusiasm for the use of LAmB in combination with other antifungals.

References:

  1. Diekema DJ, Messer SA, Hollis RJ, Jones RN, Pfaller MA. Activities of caspofungin, itraconazole, posaconazole, ravuconazole, voriconazole, and amphotericin B against 448 recent clinical isolates of filamentous fungi. J Clin Microbiol. 2003 Aug;41(8):3623-6. doi: 10.1128/jcm.41.8.3623-3626.2003. PMID: 12904365; PMCID: PMC179829.
  2. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, Kern WV, Marr KA, Ribaud P, Lortholary O, Sylvester R, Rubin RH, Wingard JR, Stark P, Durand C, Caillot D, Thiel E, Chandrasekar PH, Hodges MR, Schlamm HT, Troke PF, de Pauw B; Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002 Aug 8;347(6):408-15. doi: 10.1056/NEJMoa020191. PMID: 12167683.
  3. Herbrecht R, Patterson TF, Slavin MA, Marchetti O, Maertens J, Johnson EM, Schlamm HT, Donnelly JP, Pappas PG. Application of the 2008 definitions for invasive fungal diseases to the trial comparing voriconazole versus amphotericin B for therapy of invasive aspergillosis: a collaborative study of the Mycoses Study Group (MSG 05) and the European Organization for Research and Treatment of Cancer Infectious Diseases Group. Clin Infect Dis. 2015 Mar 1;60(5):713-20. doi: 10.1093/cid/ciu911. Epub 2014 Nov 19. PMID: 25414266.
  4. Steinbach WJ, Benjamin DK Jr, Kontoyiannis DP, Perfect JR, Lutsar I, Marr KA, Lionakis MS, Torres HA, Jafri H, Walsh TJ. Infections due to Aspergillus terreus: a multicenter retrospective analysis of 83 cases. Clin Infect Dis. 2004 Jul 15;39(2):192-8. doi: 10.1086/421950. Epub 2004 Jun 28. PMID: 15307028.
  5. Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis. 2008 Jan 15;46(2):201-11. doi: 10.1086/524669. PMID: 18171251.
  6. Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, Bow EJ, Rahav G, Neofytos D, Aoun M, Baddley JW, Giladi M, Heinz WJ, Herbrecht R, Hope W, Karthaus M, Lee DG, Lortholary O, Morrison VA, Oren I, Selleslag D, Shoham S, Thompson GR 3rd, Lee M, Maher RM, Schmitt-Hoffmann AH, Zeiher B, Ullmann AJ. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016 Feb 20;387(10020):760-9. doi: 10.1016/S0140-6736(15)01159-9. Epub 2015 Dec 10. PMID: 26684607.
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  8. Walsh TJ, Raad I, Patterson TF, Chandrasekar P, Donowitz GR, Graybill R, Greene RE, Hachem R, Hadley S, Herbrecht R, Langston A, Louie A, Ribaud P, Segal BH, Stevens DA, van Burik JA, White CS, Corcoran G, Gogate J, Krishna G, Pedicone L, Hardalo C, Perfect JR. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis. 2007 Jan 1;44(1):2-12. doi: 10.1086/508774. Epub 2006 Nov 28. PMID: 17143808.
  9. Jung DS, Tverdek FP, Kontoyiannis DP. Switching from posaconazole suspension to tablets increases serum drug levels in leukemia patients without clinically relevant hepatotoxicity. Antimicrob Agents Chemother. 2014 Nov;58(11):6993-5. doi: 10.1128/AAC.04035-14. Epub 2014 Sep 8. PMID: 25199774; PMCID: PMC4249440.
  10. Cornely OA, Maertens J, Bresnik M, Ebrahimi R, Ullmann AJ, Bouza E, Heussel CP, Lortholary O, Rieger C, Boehme A, Aoun M, Horst HA, Thiebaut A, Ruhnke M, Reichert D, Vianelli N, Krause SW, Olavarria E, Herbrecht R; AmBiLoad Trial Study Group. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis. 2007 May 15;44(10):1289-97. doi: 10.1086/514341. Epub 2007 Apr 9. PMID: 17443465.
  11. Baddley JW, Pappas PG. Antifungal combination therapy: clinical potential. Drugs. 2005;65(11):1461-80. doi: 10.2165/00003495-200565110-00002. PMID: 16033288.
  12. Maertens J, Glasmacher A, Herbrecht R, Thiebaut A, Cordonnier C, Segal BH, Killar J, Taylor A, Kartsonis N, Patterson TF, Aoun M, Caillot D, Sable C; Caspofungin Combination Therapy Study Group. Multicenter, noncomparative study of caspofungin in combination with other antifungals as salvage therapy in adults with invasive aspergillosis. Cancer. 2006 Dec 15;107(12):2888-97. doi: 10.1002/cncr.22348. PMID: 17103444.
  13. Kontoyiannis DP, Hachem R, Lewis RE, Rivero GA, Torres HA, Thornby J, Champlin R, Kantarjian H, Bodey GP, Raad II. Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies. Cancer. 2003 Jul 15;98(2):292-9. doi: 10.1002/cncr.11479. PMID: 12872348.
  14. Marr KA, Boeckh M, Carter RA, Kim HW, Corey L. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis. 2004 Sep 15;39(6):797-802. doi: 10.1086/423380. Epub 2004 Aug 27. PMID: 15472810.
  15. Singh N, Limaye AP, Forrest G, Safdar N, Muñoz P, Pursell K, Houston S, Rosso F, Montoya JG, Patton P, Del Busto R, Aguado JM, Fisher RA, Klintmalm GB, Miller R, Wagener MM, Lewis RE, Kontoyiannis DP, Husain S. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Transplantation. 2006 Feb 15;81(3):320-6. doi: 10.1097/01.tp.0000202421.94822.f7. PMID: 16477215.
  16. Marr KA, Schlamm HT, Herbrecht R, Rottinghaus ST, Bow EJ, Cornely OA, Heinz WJ, Jagannatha S, Koh LP, Kontoyiannis DP, Lee DG, Nucci M, Pappas PG, Slavin MA, Queiroz-Telles F, Selleslag D, Walsh TJ, Wingard JR, Maertens JA. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med. 2015 Jan 20;162(2):81-9. doi: 10.7326/M13-2508. Erratum in: Ann Intern Med. 2015 Mar 17;162(6):463. Erratum in: Ann Intern Med. 2019 Feb 5;170(3):220. PMID: 25599346.
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