Implementation of Pharmacist-Driven Antifungal Stewardship Program in a Tertiary Care Hospital

ABSTRACT

Antifungal stewardship (AFS) is recommended to reduce the inappropriate use of antifungal drugs. In this study, the role of AFS in providing appropriate antifungal therapy was evaluated. This study included three periods, consisting of observation, feedback/education, and daily AFS activities. In the observation period, the use of systemic antifungals was evaluated for a baseline measurement of appropriateness. In the second period, monthly meetings were organized to provide feedback and education to physicians regarding antifungal therapy and the rate of adherence to the clinical guidelines. In the final period, a clinical pharmacist participated in daily ward rounds to evaluate the appropriateness of the antifungal therapy. A scoring system for appropriateness was used for comparison between the three periods. Four hundred eighteen episodes of antifungal therapy were evaluated. Baseline demographics of patients were similar in all three periods for age, gender, and the number of comorbidities. The indications for antifungal use were for prophylaxis in 22.7%, Candida infections in 58.6%, and invasive mold infections in 18.7%. During the third period, 157 (78.9%) recommendations were made and 151 (96.2%) were accepted. The overall appropriateness of antifungal use increased significantly for prophylaxis (30.8%, 17.9%, and 46.3%; P = 0.046) and treatment of fungal diseases (27.8%, 32.4%, and 71.9%; P < 0.001) between the first, second, and third periods, respectively. The 30-day mortality was not significantly changed between the three periods (19%, 15.6%, and 27.5%; P = 0.050). Appropriateness in antifungal therapy can be augmented by the integration of an AFS program. A team-based evaluation of fungal infections and assessment of patients by a clinical pharmacist with a therapeutic perspective may help to increase the quality of antifungal therapy.

INTRODUCTION

Antimicrobial stewardship (AMS) programs aim to maintain adequate antimicrobial usage and thereby contribute to the prevention of antimicrobial resistance, improvement in health care costs, and decreases in morbidity and mortality (1). Studies on the implementation of AMS programs generally focused on antibacterial usage; however, inappropriate use of antifungals also puts a significant burden on therapies (2). It was shown that up to 74% of antifungal drug use can be inappropriate in tertiary care hospitals (3, 4). Therefore, the establishment of antifungal stewardship (AFS) programs has been recommended in recent clinical guidelines (5). Specific tools (European Confederation of Medical Mycology EQUAL Scores) for antifungal stewardship and for measuring guideline adherence have also been developed (6–8).

The initial stage of an AFS program is the implementation of practice guidelines and supportive educational activities (9). Preprescription authorization, postprescription review, and feedback are the core components of stewardship according to the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) guidelines (10). Several studies showed that lack of adherence to the guideline recommendations can affect clinical outcomes negatively (11–13). Adopting and implementing reliable guidelines and promoting and evaluating adherence to these guidelines are considered the most effective approaches provided by AFS programs. Moreover, the risk of invasive fungal diseases (IFDs) is high in patients with severe comorbidities where polypharmacy is common, and the drug-drug interactions are of concern, particularly in patients who receive triazole antifungal drugs. One of the major goals of AFS would be decreasing the rate of major interactions between antifungal drugs and other drugs.

In this study, we evaluated the impact of AFS activities on the appropriateness of antifungal therapy in terms of dose, duration, route of administration, and drug-drug interactions in a university hospital.

RESULTS

In this study, 105 (n = 84 patients), 109 (n = 101 patients), and 204 (n = 192 patients) episodes of antifungal therapy were assessed in the first, second, and third study periods (consisting of observation, feedback/education, and daily AFS activities), respectively. Baseline demographics of patients were similar in the three periods for age (median values [interquartile ranges {IQR}] of 60 [44.5 to 68], 57 [45 to 66.5], and 60 [48 to 70] years; P = 0.404), gender (38 [45.2%], 41 [40.6%], and 93 [48.4%] female; P = 0.388), and number of comorbidities (mean values ± standard deviations [SD], 2.8 ± 2.03, 2.2 ± 1.67, and 2.7 ± 1.76; P = 0.825). Three hundred sixty-six (97.1%) of 376 patients had at least one comorbid disease. The number of patients followed in intensive care units (ICUs) in the third period increased, but this did not reach statistical significance. The most common risk factor for IFDs was the presence of a central venous catheter (CVC) in 163 (39.0%) patients, followed by hematological malignancy in 128 (30.6%) (Table 1). In the third period, 20.3% (n = 39) of patients had coronavirus disease 2019 (COVID-19), and 36 (92.3%) were hospitalized in ICUs.

TABLE 1.

Categorization of antifungal therapy episodes according to department and risk factors for invasive fungal infections

Department or risk factor	No. (%) of episodes assessed in indicated period			P value
	1st (n = 105)	2nd (n = 109)	3rd (n = 204)
Departments
Oncology	53 (50.5)	49 (45.0)	88 (43.1)	0.995
Medical	35 (33.3)	43 (39.4)	84 (41.2)
Surgical	17 (16.2)	17 (15.6)	32 (15.7)
ICU	37 (35.2)	39 (35.8)	96 (47.1)	0.136
Non-ICU	68 (64.8)	70 (64.2)	108 (52.9)
Risk factors
Central venous catheter	32 (30.5)	45 (41.3)	86 (42.2)	0.116
Surgery in the last 3 mo	26 (24.8)	19 (17.4)	20 (9.8)	0.002
Corticosteroid use	31 (29.5)	32 (29.4)	59 (28.9)	0.993
Total parenteral nutrition	24 (22.9)	14 (12.8)	36 (17.6)	0.159
Renal replacement therapy	8 (7.6)	7 (6.4)	12 (5.9)	0.841
Neutropenia (<500/μl)	26 (24.8)	25 (22.9)	29 (14.2)	0.042
Solid tumor	11 (13.1)	24 (23.8)	55 (28.6)	0.023
HSCTa	13 (9.6)	14 (9.9)	21 (8.8)	0.516
Hematological malignancy	32 (38.1)	41 (40.6)	55 (28.6)	0.080
COVID-19	0 (0.0)	0 (0.0)	39 (19.1)

^aHSCT, hematopoietic stem cell transplantation.

Antifungal drugs were used for therapy of IFDs more frequently than for prophylaxis (77.3% versus 22.7%). Candidemia and suspicion of invasive candidiasis were identified, which resulted in 87 (20.8%) and 83 (19.9%) antifungal therapy episodes, respectively (Table 2). The indication for antifungal therapy was invasive pulmonary aspergillosis (IPA) in 66 patients; 77.2% (51 out of 66) were diagnosed with IPA according to the consensus definitions, and the remaining had radiological and/or microbiological findings suggesting IPA but did not meet consensus definitions. Mucorales was isolated from biopsy specimens in two patients, and six patients were diagnosed with mucormycosis based on radiological findings.

TABLE 2.

Types of fungal infections in antifungal treatment episodes

Type of fungal infection	No. (%) of episodes in indicated period			P value
	1st (n = 105)	2nd (n = 109)	3rd period (n = 204)
Candidemia	21 (20.0)	27 (24.8)	39 (19.1)	0.193
Invasive pulmonary aspergillosis	18 (17.1)	13 (11.9)	35 (17.2)
Urinary tract infection	11 (10.5)	8 (7.3)	21 (10.3)
Mucormycosis	4 (3.8)	2 (1.8)	2 (1.0)
Oropharyngeal candidiasis	3 (2.9)	11 (10.1)	10 (4.9)
Suspected invasive candidiasis	16 (15.2)	17 (15.6)	50 (24.5)
Prophylaxis	26 (24.8)	28 (25.7)	41 (20.1)
Othera	6 (5.7)	3 (2.8)	6 (2.9)

^aOther fungal infections included intrabdominal candidiasis, Candida infections involving soft tissues and prosthetic joints, panophthalmitis, and fungal chorioretinitis.

During the third period, 199 recommendations were made for 97 (47.5%) therapy episodes; of those, 157 (78.9%) were related to antifungal therapy. Among 157 antifungal-related recommendations, 151 (96.2%) were accepted (Table 3). The mean numbers of potential drug-drug interactions (pDDIs) decreased in the third period for total and moderate interactions (Table 4).

TABLE 3.

AFS recommendations and acceptance rates

Type of recommendation	No. (%) of recommendations:
	Made (n = 157)	Accepted (n = 151)
Related to fungal infection
Diagnosis	3 (1.9)	1 (33.3)
Treatment	108 (68.8)	104 (96.3)
Follow-up	46 (29.3)	46 (100)
Related to treatment
Initiation of treatment	9 (5.7)	9 (100)
Discontinuation of treatment	25 (15.9)	22 (88.0)
De-escalation	12 (7.6)	11 (91.7)
Drug selection	2 (1.3)	2 (100)
Dose increase	15 (9.6)	15 (100)
Dose decrease	10 (6.54)	10 (100)
Loading-dose selection	8 (5.1)	8 (100)
Administration route	6 (3.8)	6 (100)
Therapeutic drug monitoring	23 (15.9)	23 (100)
pDDIa	13 (9.0)	13 (100)
Adverse effects	1 (0.6)	1 (100)
Prescribing error in the order	3 (1.9)	3 (100)
Request for laboratory or radiological examination	30 (19.1)	28 (93.3)

^apDDI, potential drug-drug interaction.

TABLE 4.

Administration routes and pDDIs of antifungals in each period

Parameter	Value in indicated period			P value
	1st (n = 135)	2nd (n = 142)	3rd (n = 238)
Administration route [no. of antifungal drugs (%)]
Parenteral	106 (78.5)	110 (77.5)	184 (77.3)	0.962
Oral	29 (21.5)	32 (22.5)	54 (22.7)
Comedications (mean no./drug ± SD)	10.4 ± 4.42	9.2 ± 3.47	10.0 ± 3.93	0.061
pDDIsa (mean no. ± SD)
Total	4.2 ± 2.59	3.3 ± 1.94	2.18 ± 2.26	0.035
Major	0.7 ± 1.18	0.5 ± 0.79	0.5 ± 0.86	0.819
Moderate	3.1 ± 1.84	2.5 ± 1.50	1.5 ± 1.63	0.005
Minor	0.4 ± 0.62	0.4 ± 0.59	0.2 ± 0.44	0.427

^apDDIs, potential drug-drug interactions.

The overall appropriateness of antifungal use increased significantly in the third period compared with the remaining two periods (Table 5). Statistically significant increases were detected for both prophylaxis (30.8%, 17.9%, and 46.3%, respectively, in the three periods; P = 0.046) and treatment of fungal diseases (27.8%, 32.4%, and 71.9%, respectively, in the three periods; P < 0.001). This improvement was achieved in antifungal drug choice, dosage, and duration of therapy during the third period. The appropriateness of antifungal use according to the type of fungal infection (except for mucormycosis and suspected invasive candidiasis) increased significantly in the third period compared with the other periods (P < 0.05). With regard to the antifungal drug classes and in terms of appropriateness, there were significant improvements for the azoles and echinocandins (P < 0.001), whereas the appropriateness for liposomal amphotericin B use was similar in all periods (P = 0.174). The most commonly used antifungal drug in all treatment periods was fluconazole (Table 6). The consumption rates (with 95% confidence intervals [CI]) for anidulafungin (0.69 [0.58 to 0.81], 0.86 [0.74 to 0.99], and 1.11 [1.00 to 1.22]) and caspofungin (1.51 [1.35 to 1.69], 1.93 [1.75 to 2.13], and 2.43 [2.27 to 2.60]) increased, whereas the rates for fluconazole (3.55 [3.30 to 3.82], 2.95 [2.72 to 3.20], and 2.37 [2.21 to 2.53]) and liposomal amphotericin B (1.87 [1.69 to 2.06], 1.52 [1.35 to 1.69], and 1.10 [0.99 to 1.21]) decreased in the first, second, and third periods, respectively.

TABLE 5.

Appropriateness of antifungal therapies

Item	No. (%) of evaluated therapy episodes or length of treatment in indicated period			P value
	1st (n = 105a)	2nd (n = 109a)	3rd (n = 204a)
Overall appropriateness (no. of episodes per 1st, 2nd, 3rd period)	32 (30.5)	29 (26.6)	128 (62.7)	<0.001
Indication	100 (95.2)	103 (94.5)	190 (93.1)	0.739
Drug choice	96 (91.4)	99 (90.8)	200 (98.0)	0.022
Dosage	62 (59.0)	81 (74.3)	192 (94.1)	0.001
Microbiologic adjustment, if possible (n = 47, 50, 95)	43 (91.5)	43 (86.0)	92 (96.8)	0.054
Administration route (n = 29, 35, 46)	10 (34.5)	18 (51.4)	23 (50.0)	0.324
Length of therapy (n = 89, 97, 153)	57 (64.0)	56 (57.7)	115 (75.2)	0.013
Switch to another antifungal drug	25 (23.8)	26 (23.9)	27 (13.2)	0.021
Unresponsiveness to first-line antifungal treatment	15 (14.3)	8 (7.3)	11 (5.4)	0.033
Antifungal-related adverse reaction	6 (5.7)	3 (2.8)	7 (3.4)	0.508
30-day mortality	20 (19.0)	17 (15.6)	56 (27.5)	0.050
Duration of antifungal treatment periods [median no. of days (IQR)]	13 (8.25–19.0)	14 (9.0–20.0)	14 (10.0–19.0)	0.560

^aOr value for subgroup as indicated.

TABLE 6.

Antifungal drugs used in study periods

Drug	No. (%) of antifungal drugs in indicated period			P value
	1st (n = 135)	2nd (n = 142)	3rd (n = 238)
Fluconazole	51 (37.8)	60 (42.3)	84 (35.3)	0.400
Voriconazole	17 (12.6)	16 (11.3)	41 (17.2)	0.219
Posaconazole	9 (6.7)	12 (8.5)	16 (6.7)	0.823
Caspofungin	21 (15.6)	25 (17.6)	56 (23.5)	0.132
Micafungin	12 (8.9)	1 (0.7)	0 (0.0)
Anidulafungin	8 (5.9)	16 (11.3)	26 (10.9)	0.223
Liposomal amphotericin B	15 (11.1)	11 (7.7)	12 (5.0)	0.153
Combinations	2 (1.4)	1 (0.7)	3 (1.2)

DISCUSSION

This study demonstrated that implementation of an AFS program, which consisted of feedback and education and daily AFS activities, increased the appropriateness of antifungal therapy in a tertiary care hospital.

The relevance of indications according to the guidelines was not different in the three periods. This is somewhat expected, because the indications for antifungal therapy have been evaluated by infectious disease (ID) specialists as a daily routine practice for years in the hospital where the study was performed. However, the rate of switching to another antifungal drug and, particularly, switching because of unresponsiveness to the first-line therapy decreased significantly in the third period. On the other hand, the changes in the consumption rates, such as the decrease in fluconazole consumption and increase in echinocandin consumption, were probably related to the feedback by the AFS team about the increasing rate of non-albicans Candida species and continued emphasis on adherence to the guidelines.

The consumption rate of intravenous voriconazole decreased in the second period, with a slight increase in the consumption of oral voriconazole. Therapeutic drug monitoring (TDM) of voriconazole became available in the second period, which might be responsible for this finding. The consumption rate of oral voriconazole decreased and intravenous voriconazole use increased in the third period. This could be explained by the introduction of a new group of patients, those with COVID-19-associated pulmonary aspergillosis (CAPA). They were all in serious condition in the ICUs, and intravenous administration was required. Although pDDIs in the ICUs had the potential to trigger liposomal amphotericin B in the therapy of CAPA, there was frequent feedback by the AFS team about TDM of voriconazole and pDDIs and a significant decrease in the consumption rate of liposomal amphotericin B. This allowed an increase in the rate of guideline adherence for IPA. Potential DDIs, particularly with voriconazole, can cause the risk of failure of therapy or toxicity (14). In particular, contraindicated and major pDDIs that are clinically significant require intervention (15). In this study, both providing information about pDDIs in feedback and education meetings and daily evaluation of pDDIs in the third period helped to achieve this improvement.

Twenty percent of the AFS recommendations were about the dose of the drugs, with an acceptance rate of 100%. This was followed by discontinuation of the antifungal drugs, with an acceptance rate of 88%. This resulted in improvement in appropriate dosing and duration of therapy, as well as switching from the intravenous route to the oral route. These findings were consistent with the results of previous studies, where recommendations were performed mainly for antifungal drug change, therapy withdrawal, discontinuation of an antifungal drug in combined therapy, switching to the oral route, and dose modifications (16–20).

In the study of Cappelletty and Jacobs, the rate of inappropriate use of antimicrobials and the mean duration of therapy increased in the absence of active pharmacist involvement in antimicrobial stewardship (21). In contrast, the study of Samura et al. found that the rate of optimal antifungal drug usage increased and the duration of antifungal therapy decreased with the implementation of an AFS program (22). These findings were supported by this study too, except for the decreased duration of antifungal treatment. This can be related to differences in study designs and the patient populations included. The degree of adherence to AFS recommendations has been reported to be between 40 and 98.1% (16, 17, 19). A decrease in the mortality rate with the involvement of the AFS team was reported in one study (17), whereas the 30-day mortality rate was not changed significantly in the post-AFS period (30.0%) compared to the pre-AFS period (40.9%) in the study of Kawaguchi et al. (16). This was also the case in another study, which used a methodology similar to ours; the mortality rate and the mean duration of hospitalization were not changed between the study periods (23). In the current study, the acceptance rate of AFS recommendations was found to be 96.2%; however, there was no decrease in the 30-day mortality rate. The high rate of patients with severe comorbidities, as well as the COVID-19 outbreak during the third period, can explain this situation. Thirty-nine of 192 patients who were followed in the third period were diagnosed with COVID-19, and 36 required ICU support. Mortality related to CAPA in the ICU was reported as 54.9% in a recent meta-analysis (24). Considering this high rate of mortality, it is reasonable to consider that CAPA contributed to 30-day mortality in the third period of this study. When an analysis was performed by excluding COVID-19 patients, the mortality rate in the third period was found to be 23%; this was not significantly different from the other study periods (P = 0.311). Improving the mortality by employing an AFS team is an audacious idea that would require randomization and control of several confounding factors to investigate, which can be very difficult in a real-life setting.

In the study of Valerio et al. (18), inappropriate choice of antifungal drug, duration of therapy, and microbiological adjustment were the most frequent therapy problems. The median duration of antifungal therapy was 14 days (interquartile range, 7 to 26); recommendations were made for 40.4% of patients, and at least one inappropriateness was found in 45% of antifungal courses. The findings were similar in this study, where recommendations were made for 47.5% of therapy periods in the third period and 69.5% of therapies had at least one inappropriateness in the first period, compared to 30.4% in the third period. Moreover, Valerio et al. (25) indicated that daily evaluation of each antifungal therapy is time consuming, and “switch to oral therapy” should be scored in the parameters. However, some patients can be treated with oral antifungals from the beginning of the therapy, and modification of this item may provide ease of use. Furthermore, pharmacokinetic parameters can change dynamically in critically ill patients. Therefore, a daily evaluation becomes important and required to maintain appropriate antifungal therapy.

This study has several limitations. It was performed in a single tertiary-care center, and thus, the results may not be applicable to other institutions, such as general or nonspecialized hospitals. Moreover, the study analyzed about 400 consecutive therapy periods from the perspective of a nonrandomized and cross-sectional design, and therefore, potential epidemiological changes during the study period could not be controlled. Although most of the appropriateness items improved in the third period, the mortality rate increased. The COVID-19 pandemic may had have unforeseen effects in the third period of this study, since our hospital served as a pandemic hospital.

In conclusion, our study showed that a pharmacist-driven AFS program is practical and achievable and has the potential to become a part of the standard of care in tertiary care hospitals where a high number of patients with increased risk factors of IFDs are managed. Considering the workload and variety of patients encountered in ward rounds, team-based evaluation of fungal infections, including feedback and support from a clinical pharmacist (CP), may help to increase the quality of antifungal therapies. In this setting, implementation of the pharmacist-driven AFS program was feasible but of relatively limited advantage in terms of clinical outcome. The implementation of an AFS can increase the rate of appropriateness in antifungal therapies in terms of drug choice, dosage, and duration of therapy and can prevent pDDIs.

MATERIALS AND METHODS

This prospective, quasiexperimental (before-and-after) study was conducted at a tertiary care university hospital in Ankara, Turkey, between January 2019 and November 2020. The adult care hospital has 1,040 beds, including eight intensive care units (ICU)s with 143 beds, and the oncology hospital has 131 beds including a hematopoietic stem cell transplantation (HSCT) ward with 16 beds and an ICU with 8 beds. Antimicrobial agents are ordered through a computerized order system in which the indication of dose, administration route, and time is compulsory. The authorization of antifungal orders—except for oral fluconazole—is restricted to infectious disease (ID) specialists in Turkey. Patients with suspicion of invasive fungal diseases (IFDs) are subject to consultation at the bedside by ID specialists and followed until the cessation of therapy, resolution of the symptoms, or discharge. There are local diagnostic and management guidelines in the hospital database that were prepared by a multidisciplinary team that was led by ID specialists. Although there is no formal regulation, a close collaboration exists between ID, radiology, and medical mycology specialists. Participation of clinical pharmacists (CPs) in the ID ward round is limited by the number of CPs.

The study consisted of three periods: first, an observation (4 months) period; second, provision of feedback and education (4 months); and third, implementation of the daily evaluation and recommendations (8 months). A CP was actively involved in each period of the study, where use of antifungal therapies was observed (1st period), feedback and education were provided at monthly intervals regarding adequate use of antifungals (2nd period), and the daily AFS program was implemented (3rd period).

The AFS team consisted of 2 ID specialists, 2 CPs, 2 clinical microbiologists, and 1 radiologist. During the observation period between January and May 2019, the use of systemic antifungals was recorded for a baseline assessment. The first feedback meetings were organized after the analysis of the observation period. This analysis was followed in the second period, between October 2019 and February 2020, by monthly meetings to provide feedback and education to both senior and junior physicians from the departments of infectious diseases, hematology, oncology, internal medicine, and intensive care regarding antifungal therapy and adherence to the guideline recommendations. The AFS team did not make any individualized recommendations for patients during the first two periods, in order to perform a nonbiased audit. In the third period, between March and November 2020, a CP participated in daily clinic visits in the ICUs and the internal medicine, oncology, and HSCT wards. Antifungal therapy was evaluated by CPs in terms of indication, the drug of choice, dosage, route of administration, and pDDIs according to local institutional guidelines, which were based on international guidelines and local epidemiology where necessary (26–28). The recommendations were made by consensus with the ID specialists in the AFS team. In the case of inappropriate antifungal therapies, a recommendation(s) was made on the same day. Additional support was obtained from clinical microbiology and radiology specialists if any questions were raised about the results of radiological investigations or mycology tests.

The study was approved by the Local Ethics Committee. Patients aged ≥18 years who received systemic antifungal therapies with any indication of hospitalization during the study period and who gave written consent were included. Patients who received antifungal therapies for less than 72 h were excluded.

Data on patient characteristics and antifungal therapies with pDDIs were collected prospectively. In addition, the risk factors for fungal infections were evaluated (29). Antifungal therapies were followed for at least 1 month for each patient.

Antifungal therapy indications for mold infections were defined according to the diagnosis of IFDs by consensus definitions (30–32) or with regard to radiological and/or microbiological findings of invasive mold disease that triggered antifungal therapy in ICU patients who did not meet the criteria by consensus definitions. The indications for therapy of Candida infection were the isolation of Candida species from blood culture or other sterile body fluids, isolation of Candida species from multiple nonsterile body sites in sepsis without any other evidence of IFDs (suspected invasive candidiasis), physician observation or endoscopic diagnosis of oropharyngeal plaques suggesting mucosal candidiasis, and candiduria in a febrile patient with no other explanation for fever. Antifungal use for other than these indications was considered inappropriate. The indications for antifungal prophylaxis were defined according to the European guidelines issued by the European Conference on Infections in Leukaemia (ECIL) (33).

The adequacy of antifungal therapies was assessed by a scoring system that evaluates antifungal therapy in terms of indication, choice of antifungal agent, dosage, route of administration, adjustment of therapy according to microbiological results, and length of therapy (34). For the detection and classification of pDDIs, the Drugs.com drug interactions database (https://www.drugs.com/drug_interactions.html) was used.

Mean values and standard deviations (SD) were used for data with a normal distribution, and median and interquartile range (IQR) were used if the data had a nonnormal distribution. The t test was used for evaluation of scores in subgroups. The proportion of inappropriate therapy was compared using the χ² test. All statistical tests were two tailed. The level of statistical significance was accepted as P = 0.05. All statistical analysis was performed using the Statistical Package for the Social Sciences software package (SPSS, Inc., version 23.0, Chicago, IL).

The antifungal consumption rate was measured in days of therapy per 1,000 patient-days per each study period by using the hospital database. Initiation of antifungal prophylaxis and therapy rates were measured per 100,000 patient days. OpenEpi (Open Source Epidemiologic Statistics for Public Health) version 3.01 (https://www.OpenEpi.com) was used for the analyses. The mid-P exact test was used to calculate the 95% confidence interval for each period.