Are Echinocandins superior to Triazoles for the treatment of invasive candidiasis?

As someone dually trained in intensive care and infectious disease, I have received conflicting advice on the choice between echinocandins and triazoles for invasive candidiasis during each residency. In Belgium, where triazoles resistance is rare, I was initially taught to prefer triazoles unless the patient was considered critically ill. However, during my ICU training, another infectious disease specialist advocated for empirical echinocandin use in all patients. Even more puzzling was that both lecturers cited the same studies and the same 2016 IDSA guidelines. In this post, I aim to outline this debate, starting from one central question:

Who are ‘the good, bad and ugly’ in the echinocandins versus triazoles discussion?

The 2016 IDSA guidelines recommend echinocandins as initial therapy for candidemia in non-neutropenic patients. However, fluconazole is considered an acceptable alternative for non-critically ill patients with a low risk of fluconazole-resistant Candida (1). By contrast, some authors argue for the universal use of echinocandins as first-line (2, 3). Let’s take a look at some of the arguments in this debate:

The BAD – arguments that should NOT be used to establish the superiority of echinocandins.

1. The review by Andes et al. (2012) (4)

This review pooled data from seven randomized trials, claiming a 30-day all-cause mortality benefit for echinocandins in treating invasive candidiasis. However, there are major flaws in this review:

• Only three studies directly compared echinocandins to other antifungal therapy (and these showed no difference in outcomes between both treatment arms). Another study compared two echinocandins against each other (5) while the remaining three trials didn’t contain an echinocandin arm at all (5). Moreover, the included trials spanned a period of 17 years, whereas echinocandins were only used in the latter half (6).

  
  

• The other conclusion of this review is already debunked. Andes et al. also suggested that central venous catheter (CVC) removal at any time improved survival. However, some major issues with their methodology were identified (7). A re-analysis of the two most recent studies, using stricter criteria, found no survival benefit (7).

2. The fungicidal effect of echinocandins

A common explanation for the superiority of echinocandins over triazoles is their fungicidal (rather than fungistatic) activity. Most likely, this reasoning is too simplistic for the following reasons:

• In vitro, amphotericin B kills Candida more rapidly and efficiently than echinocandins (8). As its toxicity has improved considerably with its liposomal formulation (9), the above reasoning would make liposomal amphotericin B the preferred choice.

  
  

• Isavuconazole demonstrates greater in vitro activity against Candida species than fluconazole (10). Furthermore, in the ACTIVE trial, the median time to negative blood cultures did not differ between isavuconazole and caspofungin (11). However, caspofungin showed superior efficacy at the end of treatment (11).

The GOOD – arguments that should be at the Forefront of the Debate

Two randomized controlled trials support the superiority of echinocandins over triazoles for the treatment of invasive candidiasis. While a critical appraisal of these studies follows, randomized controlled trials remain the highest order of evidence.

* Anidulafungin versus fluconazole – 2007 (12).

This study suggested that anidulafungin was superior to fluconazole in treatment success at the end of intravenous therapy. The fragility index was 5, indicating a robust result. The primary difference between both treatment arms was a higher persistence of positive cultures in the fluconazole group.

Some comments about this study:

- A potential center effect could not be demonstrated by multiple statistical tools. However, excluding this center from the analysis, eliminated anidulafungin’s apparent superiority.

- Mortality did not differ significantly between both groups, though there was a trend towards increased survival in the echinocandin group.

- Outcomes were similar in patients with APACHE II score > 20, limiting conclusions about critically ill patients.

- Pathogen-wise, the only significant difference was observed in susceptible C. albicans, leading some to question whether fluconazole dosing was optimal (13).

* Caspofungin versus isavuconazole – 2018 (11).

This trial demonstrated that caspofungin is not non-inferior to isavuconazole for the treatment of invasive candidiasis, though this difference disappeared two weeks after the end of treatment. To date, this remains the only randomized controlled trial to show an undisputed difference between the two anti fungal classes, with a fragility index of 3.

Key considerations:

- As in the previous study, patients could receive up to 48 hours of systemic antifungal therapy before inclusion.

- The median time to negative blood cultures and the rate of persistent candidemia were similar in both groups.

- Mortality did not differ significantly between the two treatment arms.

- High Body mass index was associated with worse outcomes in the isavuconazole group, raising concerns about potential under-dosing (6).

THE UGLY – Arguments that should make you think before taking a Definitive Stance

While echinocandins have become first-line treatment for invasive candidiasis in recent years (2,3,6,9), several unresolved issues warrant caution:

a) No mortality benefit

No randomized controlled trial has demonstrated a survival advantage for echinocandins over triazoles in invasive candidiases (14). Some authors attribute this to the small sample size of the different studies (2), feeling supported by the mortality trend observed in the 2007 trial (12). However, a recent meta-analysis of 13 trials concluded that the lack of survival benefit is unlikely due to underpowering (14).

b) No clear advantage in critically ill patients

As mentioned before, outcomes in the 2007 trial were similar between anidulafungin and fluconazole in patients with an APACHE II-score > 20 (12). Even the 2012 review did not show any mortality difference in patients with APACHE II-score > 24 (4) whereas retrospective studies have yielded mixed results (6,15). These findings suggest that co-morbidities may play a more significant role than the choice of antifungal agent in critically ill patients (14,16).

c) Unclear biological basis of superiority

The fungicidal effect of echinocandins alone does not fully explain their apparent superiority over triazoles. Other proposed mechanisms include the post-antifungal effect of echinocandins or their activity against Candida biofilms (14). However, a definitive biological rationale for their advantage remains elusive (14). Additionally, the position of liposomal amphotericin B in this context is still undefined.

d) Step-down to triazoles?

Current guidelines recommend stepping down to triazoles once the patient’s clinical state has stabilized and candidemia is microbiologically cleared (1). If echinocandins were truly clinically superior, however, it would be logical to continue them throughout the entire treatment course. This approach has become more feasible with the introduction of rezafungin, a weekly-administered echinocandin. Additionally, a recent meta-analysis demonstrated the non-inferiority of this new drug compared to caspofungin (17).

e) Development of resistance

Several studies observed the emergence of resistant Candida strains, as early as seven days after the start of echinocandin therapy (6,9). Not only did this lead to resistance to echinocandins, but also to reduced susceptibility to triazoles (6). Widespread use of echinocandins for all cases of invasive candidiasis could therefore drastically limit future treatment options.

My view: Invasive candidiasis is a serious infection requiring prompt and adequate treatment, with source control being the most critical intervention (17). Based on the local epidemiology, I would consider triazoles as first-line therapy for clinically stable patients. For critically ill patients or in regions with high rates of triazole-resistant Candida species, I would advocate for an echinocandin-first strategy.

References:

 1. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Feb 15;62(4):e1-50.

 2. Andes D. Has the Optimal Therapy for Invasive Candidiasis Now Been Defined? Clin Infect Dis. 2019 May 30;68(12):1990-1992.

 3. Junco SJ, Chehab S, Giancarelli A, et al. Adherence to National Consensus Guidelines and Association with Clinical Outcomes in Patients with Candidemia. Infect Dis (Auckl). 2021 Jun 7;14:11786337211018722.

 4. Andes DR, Safdar N, Baddley JW, et al. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis. 2012 Apr;54(8):1110-22.

 5. Cisneros JM, Neth O, Pachón J. Selection bias in Andes et al. Clin Infect Dis. 2012 Sep;55(6):893-4; author reply 894-5.

 6. Theodore DA, Henneman AD, Loo A, et al. Initial micafungin treatment does not improve outcomes compared to fluconazole treatment in immunocompromised and critically ill patients with candidaemia. J Antimicrob Chemother. 2024 Aug 1;79(8):1877-1884.

 7. Anaissie E, Nucci M. Far-reaching conclusions based on weak and missing data. Clin Infect Dis. 2012 Sep;55(6):890-3; author reply 894-5.

 8. Sobel JD, Revankar SG. Echinocandins--first-choice or first-line therapy for invasive candidiasis? N Engl J Med. 2007 Jun 14;356(24):2525-6.

 9. Maseda E, Martín-Loeches I, Zaragoza R, et al. Critical appraisal beyond clinical guidelines for intraabdominal candidiasis. Crit Care. 2023 Oct 3;27(1):382.

 10. Marcos-Zambrano LJ, Gómez A, Sánchez-Carrillo C, et al. Isavuconazole is highly active in vitro against Candida species isolates but shows trailing effect. Clin Microbiol Infect. 2020 Nov;26(11):1589-1592.

 11. Kullberg BJ, Viscoli C, Pappas PG, et al. Isavuconazole Versus Caspofungin in the Treatment of Candidemia and Other Invasive Candida Infections: The ACTIVE Trial. Clin Infect Dis. 2019 May 30;68(12):1981-1989.

 12. Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007 Jun 14;356(24):2472-82.

 13. Aberegg SK, O'Brien JM Jr. Anidulafungin and fluconazole for candidiasis. N Engl J Med. 2007 Sep 27;357(13):1347; author reply 1348.

 14. Demir KK, Butler-Laporte G, Del Corpo O, et al. Comparative effectiveness of amphotericin B, azoles and echinocandins in the treatment of candidemia and invasive candidiasis: A systematic review and network meta-analysis. Mycoses. 2021 Sep;64(9):1098-1110.

 15. Ferrada MA, Quartin AA, Kett DH, et al. Candidemia in the critically ill: initial therapy and outcome in mechanically ventilated patients. BMC Anesthesiol. 2013 Oct 30;13(1):37.

 16. Bennett JE, Powers JH. Candidemia in the ICU: Does Initial Antifungal Matter? Crit Care Med. 2018 Mar;46(3):482-483.

 17. Al Diab Al Azzawi M, Abdat W, Alhamed A, et al. Rezafungin vs caspofungin for the treatment of invasive candidiasis: A systematic review and meta-analysis. Diagn Microbiol Infect Dis. 2025 Jul 5;113(3):116994.

 18. Bassetti M, Righi E, Ansaldi F, et al. A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality. Intensive Care Med. 2014 Jun;40(6):839-45.