Has the optimal therapy for invasive candidiasis now been defined?

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David Andes

Department of Medicine and Microbiology and Immunology,

University of Wisconsin

1685 Highland Ave, Madison, WI 53705

dra@medicine.wisc.edu

© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of
America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
 Invasive candidiasis remains the most prevalent health-care related fungal

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infection [1, 2]. Despite recent advances in antifungal pharmacology, the successful

management of invasive candidiasis continues to pose a difficult challenge to clinicians

and crude mortality rates remain near 50%. Epidemiologic studies have linked

numerous immutable host, pathogen, and management factors to poor patient

outcomes [3-5]. The management strategies shown to exhibit the greatest impact on

patient survival are the extirpation of medical devices, the control of intra-abdominal

infection sources, and the early initiation of antifungal therapy [6-9]. Despite the

development of nearly a dozen antifungal drugs from three mechanistic classes over the

past several decades, randomized comparative trials have failed to reveal a superior

treatment.

Ten randomized trials have examined the outcome for patients with invasive

candidiasis treated with various antifungals, including two polyenes, three triazoles, and

three echinocandins [10-19]. The trial designs have been extraordinarily similar from the

standpoint of patient inclusion-exclusion criteria, as well as outcome assessments. The

most commonly utilized primary outcome has involved a composite of both clinical and

microbiologic factors determined at the end of antifungal therapy. The antifungal

comparisons have included each possible drug class combination (triazole vs polyene,

polyene vs echinocandin, triazole vs echinocandin). All of the trials have utilized a non-

inferiority design with a margin for demonstration of non-inferiority near 15%. One

difference in study design has been the patient samples sizes, which have varied by

more than two-fold (237 to 595 patients). The outcomes from these randomized trials
have also been remarkably similar, with the success for the primary endpoint ranging

from 70 to 80%. On occasion, the outcome comparisons have come close to

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demonstrating statistically significant differences. Perhaps the most compelling

example emanates from the comparison of the triazole, fluconazole to the echinocandin,

anidulafungin [10]. In this investigation, the primary outcome of global success at the

end of intravenous therapy favored the echinocandin numerically, and the initial

statistical analysis demonstrated superiority for the echinocandin arm (75.6% for

anidulafungin versus 60.2% for fluconazole, 15.4 percentage points; 95% confidence

interval [CI], 3.9 to 27.0). However, in search for a center effect, one center was

eliminated, which ultimately altered the statistical significance to non-inferior (73.2% for

anidulafungin versus 61.1% for fluconazole, 12.1 percentage points; 95% CI, −1.1 to

25.3 after consideration for center effect). The secondary mortality endpoint also

favored the echinocandin, but again the difference did not reach statistical significance

(anidulafungin 31% vs fluconazole 23%, p=0.13).

The results of these trials were subsequently assessed in meta-analyses to

further explore the possibility of a superiority among individual drugstreatment for

invasive candidiasis. Like the individual trials, significant differences were not found [20,

21]. However, the similarity in clinical design among the trials prompted investigators to

perform a pooled analysis of the primary patient data. Considering the congurence in

preclinical and clinical efficacy for antifungals belonging to the same drug class, data for

individual drugs in each class were combined [6]. Indeed, the analysis identified an

outcome advantage for echinocandin utilization as initial therapy (mortality,

echinocandin, OR 0.65 (95%CI 0.45-0.94), clinical success OR 2.33 (95% CI 1.27-

4.35). This finding is consistent with preclinical experimental models suggesting the

superiority of the echinocandin class for the treatment of candidiasis [22]. These data,

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in part, led the IDSA guideline committee to recommend initial therapy with an

echinocandin, followed by subsequent stepdown to an oral triazole after patient

improvement for those with predicted triazole success based upon the species identified

or direct susceptibility testing [23].

In the current journal issue, Kullberg et al. report the results of the most recently

completed large, randomized trial for treatment of invasive candidiasis. The

investigation compared the new triazole, isavuconazole, to caspofungin, one of three

echinocandins approved for management of invasive candidiasis. Isavuconazole

exhibits broad-spectrum antifungal activity, including activity against Candida species,

similar to other available triazoles [24]. It is also active against filamentous fungi and

recently received approval for management of infection due to Aspergillus species and

zygomycetes [25, 26]. The current candidiasis study was in large part similar in design,

conduct, and analysis to previous invasive candidiasis trials. However, non-inferiority

comparison for the primary endpoint favored the echinocandin over the triazole

(successful overall response at EOIVT 60.3% in the isavuconazole arm and 7.1.% in the

caspofungin arm, -10.8 [-19.9, -1.8]). This large randomized trial is the first to identify a

statistically significant difference in the treatment arms for the primary endpoint. The

outcome is consistent with the pooled trial analysis, identifying improved efficacy with an

echinocandin. It is also aligns with the original analysis of the randomized trial of

anidulafungin v. fluconazole that was subsequently dismissed due to concern for center

effect [10]. Strikingly, the difference in outcome for the primary endpoint was close to
10%, which is very similar to that for the pooled analysis . Analysis of secondary

outcome measures, which included all-cause mortality, composite outcome later time

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points, and time to clearance of candidemia, were statistically similar between treatment

arms. However, the trend for each of these endpoints numerically favored the

echinocandin.

An intriguing finding for this study is that isavuconazole was favored as the oral

step-down therapy when compared to voriconazole. While the failure of voriconazole

was 15%, it was reported at only 5.8% for isavuconazole. The authors speculate that

subtherapeutic concentrations of voriconazole may have played a role.[27-29].

Unfortunately, therapeutic drug monitoring was not a component of the current trial.

This secondary analysis also raises the question of a dosing concern. The poor

outcomes observed for the isavuconazole group correlated with a BMI>25. With a fixed

dose regimen, one could speculate that exposures were insufficient due to lower drug

exposures for overweight patients.

Additional comparisons searched for an imbalance in factors that have been

previously implicated in patient outcome. However, treatment randomization for these

factors, including severity of illness, removal of vascular catheters, degree of

immunosuppression, Candida species, and minimum inhibitory concentrations (MICs)

were similar. One notable difference between the current trial and prior trials comparing

an echinocandin and a triazole was the sample size, with the current study nearly 2-fold

larger. This larger sample size may have provided a greater ability to discern drug-

class differences.
 The authors are to be commended for the thoughtful study design, analysis, and

balanced interpretation. Many will conclude the results from this large trial finally

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demonstrate the superiority of the echinocandin class for initial therapy of invasive

candidiasis. Drug use analysis demonstrates the use of echinocandins for invasive

candidiasis has been widely adopted as first line therapy [30]. This is in keeping with

the current society treatment guidelines which are strengthened by the current trial

results. However, the optimal triazole oral step-down therapy remains less clear. While

fluconazole remains the option with the greatest clinical experience, other triazoles are

often employed to provide an extended spectrum for resistant isolates, such as Candida

krusei. In this scenario, voriconazole, approved for the treatment of invasive

candidiasis, has been an attractive option. Given the performance of oral

isavuconazole as step-down therapy in this study, it may very well be a reasonable

treatment option for fluconazole-resistant isolates, drug-interactions and other toxicities.

Finally, the design of the present study with regard to sample size will be important to

consider in the planning of trials for novel drug antifungal drug classes in development.

Conflicts

Dr. Andes reports grants from Astellas, Merck, Amplyx, Scynexis, Cidara, Paratek,

Actellion, Matinas, Wockhart, Zavante, Noso, outside the submitted work.

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