Core Recommendations for Antifungal Stewardship: A Statement of the Mycoses Study Group Education and Research Consortium

CORE ELEMENT 1: ENGAGEMENT OF SENIOR MANAGEMENT LEADERSHIP TOWARD ANTIMICROBIAL STEWARDSHIP

Recommendation: Antimicrobial stewardship and antifungal stewardship goals should be integrated into hospital strategic plans and policies with senior leadership engagement, accountability, and dedicated resources to support these activities.

Senior leadership support has been shown to be a critical component of quality improvement programs, similar to AMS and infection prevention [24–28]. Over time, there has been increasing recognition of the value of senior leadership in hospital quality and safety. Leadership can both empower the stewardship programs to enact necessary changes and support expansion of stewardship goals throughout the organization by promoting engagement and awareness. In a 2013 systematic review of 122 publications, Millar and colleagues noted that high-performing hospital organizations in the US were more likely to have boards with a dedicated quality committee and have written policies, tools such as dashboards and scorecards, and established goals of quality improvement for the organization [29]. The largest hospital accreditation body in the US, The Joint Commission, has called for hospital leaders to establish a culture of safety as well as establish AMS programs as an organizational priority [30, 31]. These executive advocates should ensure that stewardship maintains a key place as part of organizational priorities as evidenced by inclusion in budgets, strategic plans, performance improvement priorities, job descriptions, and annual institutional goals. In addition, sufficient resources should be allocated to support achievement of these goals including personnel, operational resources, and information technology systems.

A recent survey of National Health Service (NHS) acute-care hospitals in England found that >50% of responding hospitals were lacking in the senior leadership component of the core elements [32]. Similarly, data from the 2015 National Healthcare Safety Network (NHSN) survey of 4569 acute and critical access hospitals in the US indicated that only 48.1% met all 7 Centers for Disease Control and Prevention (CDC) Core Elements of Antimicrobial Stewardship, and that Leadership Commitment had the second-lowest compliance rate of the core elements (67.7%). In multivariate analysis, having a written statement of commitment from the facility’s leadership was the strongest predictor of meeting all 7 CDC core elements [33].

AFS should be prominent in stewardship discussions with leadership, as antifungal use often involves key “at risk” patient populations, is expensive, and may help leverage other stewardship activities including diagnostic stewardship. Administrators are frequently faced with the challenge of prioritizing the funding of multiple competing programs that similarly aim to optimize patient care, and cost-effectiveness may not necessarily translate into dollars saved for the institution. While cost reductions should not be the primary aim of any stewardship program, cost savings may be an added benefit to the healthcare system as antimicrobial use is optimized. A compelling argument may be that the AMS program will result in cost savings but also optimize patient care [34]. A recent study reported that antifungal expenditures in the United States exceeded $9.37 billion for the years 2005–2015, and direct healthcare costs associated with fungal diseases in the US exceeded $7.2 billion in 2017 [35, 36]. Given the high cost of many antifungal agents, it is possible that cost savings realized with AFS would likely offset much of the overall costs of running an entire AMS program and help make the business case for the entire program [22, 37]. Assessing the institutional impact of AFS within the overall AMS program could be an essential and potentially influential component of discussions with leadership. Similarly, working with leadership of service lines responsible for key areas of antifungal use, such as those responsible for oncology services, may prove more successful given their influence on providers and protocols governing day-to-day utilization of these agents.

It is possible that within an organization, depending on the frequency of fungal infections encountered and complexity of the patient population, AFS might not require extensive resources over and above that dedicated to AMS already. In some cases, the natural place for AFS may be as an extension of the AMS committee. However, the AFS needs of the individual facility should be evaluated carefully and resourced accordingly. In a recent survey of AFS programs at acute-care NHS Trusts in England, 11% of participating centers reported having a dedicated AFS program, while 43% indicated that AFS was included as part of their AMS program and 26% stated that they did not have a dedicated AFS program but monitor antifungal utilization [17]. Twenty percent did not have a dedicated AFS program at all, and 27 of 34 responding facilities stated they would increase AFS activities if they could. Facilities not performing AFS indicated that this was most often due to a lack of resources such as staff time (67%) and competing priorities (48%). These barriers, as well as a lack of financial resources, have been cited repeatedly in the AMS literature.

Our authorship believes that hospital leadership should ensure an appropriate level of staffing and personnel to carry out AFS activities, where feasible and within the scope of individual institutional profiles. In an attempt to address this, several groups have published staffing models for AMS with considerations specific to healthcare settings (eg, inpatient, outpatient, long-term care) [38]. As of 2017, only 5 nations had standards for AMS staffing [39]. However, these staffing models and standards do not specifically differentiate AFS vs AMS needs and there is considerable variability in what are considered core AMS activities [38]. This remains an area of need for future investigations.

CORE ELEMENT 2: ACCOUNTABILITY AND RESPONSIBILITIES

Stewardship success hinges on having a highly functioning multidisciplinary team. This is not unique to AFS, but the team may need uniquely qualified members to incorporate the complex aspects of antifungal management. As previously mentioned, antifungal agents are often critical components of treatment protocols under the leadership of other specialties such as stem-cell or solid organ transplant and/or hematology/oncology. In addition to having defined and identified AMS leadership, engaged representatives from other areas of frequent antifungal use should be identified and incorporated as key stakeholders for AFS. Coordinating these various disciplines and the silos of care that exist is critical to the success of AFS.

As an example, antifungal prophylaxis in high-risk populations extends beyond acute hospitalization, and issues regarding antifungal drug access and acquisition in the outpatient setting become paramount in a successful therapeutic course. In these cases, failure to provide antifungal drug coverage can lead to the devastating consequence of a new IFD. Therefore, having team members that span the inpatient and outpatient settings is important. Similarly, antifungal therapy also involves many drug–drug interactions with essential treatments for underlying disease states, such as immunosuppressive agents following transplant. Any modifications desired by the AFS team should only be made after careful consideration of these other therapies and management strategies, and in consensus with the individual services. In the case of these high-risk populations, responsibility for the care of the patient lies with the primary specialties; stewarding of these antifungal agents should be included in those formal responsibilities.

Recommendation: Core members of the stewardship team should have in-depth knowledge and clinical experience in the management of invasive fungal disease (IFD) in pertinent patient populations, including fungal epidemiology and susceptibility patterns; laboratory diagnosis of IFD; spectrum and pharmacokinetics of antifungal drugs; strategies for optimizing antifungal dosing and duration; fungal surveillance; and anticipating, interpreting, and managing drug–drug interactions, antifungal toxicities, and their management, as well as interpretation of therapeutic drug monitoring. This would include, whenever possible, infectious diseases (ID) physician(s) and ID-trained pharmacist(s).

As mentioned previously, the formation of a multidisciplinary team with the necessary expertise is essential to AFS activities. Core members of the stewardship team should have in-depth knowledge and clinical experience in the management of IFD in pertinent patient populations, including fungal epidemiology and susceptibility patterns; laboratory diagnosis of IFD; spectrum and pharmacokinetics (PK) of antifungal drugs; strategies for optimizing antifungal dosing and duration; fungal surveillance; and anticipating, interpreting and managing drug–drug interactions, antifungal toxicities, and their management as well as interpretation of therapeutic drug monitoring (TDM) [40]. Involvement of knowledgeable ID consultants is important [41]. However, such expertise may not always be available within the institution and guidance may need to be obtained from outside sources. In a recent US survey, 31% of 528 responding hospitals did not have an ID physician on the stewardship committee and only 52% had an ID-trained pharmacist [42].

Similar to generalized AMS where the definition of stewardship expertise remains unclear, AFS is subject to significant challenges due to the lack of AFS-specific training programs. In limited-resource settings, it may be possible to increase involvement of ID leadership in local AFS activities by (1) contracting or resource-sharing with other hospitals for ID-trained personnel; (2) utilizing resources within a health system network, recognizing that local needs and personnel must be taken into consideration at the network level; (3) using collaborative organizations to share data and resources (eg, private/commercial consulting organizations, statewide groups in the US, or national networks in many countries); or (4) engaging telehealth support for stewardship efforts at the local level [43]. A supplemental or alternative approach when ID expertise is not available would be to identify and train local personnel in AFS principles and best practices.

Recommendation: We recommend that antifungal stewardship teams develop ongoing collaborative strategies to engage key practitioners who most frequently manage invasive fungal disease (eg, weekly clinical rounds), or include clinical specialists from high-prescribing specialties as core team members in stewardship discussions involving antifungal therapies.

Engagement with clinical specialties that involve the most frequent prescribing of antifungal therapy, either by routinely attending clinical rounds or through high visibility in key units, builds trust and communication and is key to successful stewardship of these agents [44]. Unsolicited patient care recommendations are more likely to be accepted when colleagues are viewed as team members rather than external auditors who lack direct knowledge of the patient or are unwilling to accept direct responsibility for medical decisions [40]. Many transplant physicians, intensivists, hematologists, and transplantation-oncology ID physicians acquire significant expertise in the management of IFDs and should play important roles in the AFS programs [40]. Their participation is critical for the development of effective care bundles and making daily decisions for patient management. AFS programs should engage these clinical specialists or identify “champions” within these specialties with an interest in improving the management of IFD.

Regarding implementing routine stewardship activities, the effectiveness of stewardship interventions is improved if a team member has opportunities to discuss the patient’s clinical history and plans for future surgery, transplant, and/or chemotherapy, and the potential impact of antifungal treatment on the individualized treatment regimen of their underlying disease. For example, in patients with acute myeloid leukemia, mold disease increases not only short-term mortality risk but also long-term risk of disease relapse due to disruption of therapeutic plans scheduled after complete remission achievement (eg, consolidation chemotherapy, transplantation) [45–47]. Additionally, azole antifungals may have severe drug–drug interactions with many of the small-molecule kinase inhibitors used as targeted chemotherapy in consolidation regimens or to bridge patients to hematopoietic stem cell transplantation [48]. Therefore, decisions regarding antifungal prophylaxis should not be made in a “vacuum,” but rather following multidisciplinary discussions to understand the patient’s prognosis for relapse and the future treatment approaches, in order to maintain remission of the underlying malignancy.

Frequently, these practitioners are best positioned to provide optimal diagnostic approaches and to incorporate advances in their field into the management of IFD. For example, radiologic findings often drive decisions with regard to antifungal prescribing in patients with suspected invasive pulmonary aspergillosis, even though characteristic findings of the disease on chest computed tomography (CT) (eg, nodular opacities with or without a halo sign) are neither sensitive nor specific for mold disease and may drive unnecessary empiric antifungal prescribing [49, 50]. Improvement in the specificity and sensitivity of radiological detection of fungal lesions will likely improve AFS performance. Stanzani and colleagues reported that improved radiologic assessment using CT pulmonary angiography, which can distinguish angioinvasive fungal disease from more common bacterial pneumonia or other non-angioinvasive processes in the lung, supported reduction in empiric antifungal use among high-risk hematology populations with European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG)–defined possible aspergillosis [51]. Similarly, fluorodeoxyglucose positron emission tomography/CT may detect occult or undiagnosed disseminated IFD in more than one-third of patients and detect resolution of the infection sooner than conventional CT, possibly supporting earlier discontinuation of antifungal therapy [52–55].

CORE ELEMENT 3: AVAILABLE EXPERTISE ON INFECTION MANAGEMENT

As discussed above, it is important to have individuals with antifungal expertise as AMS committee members. Although not previously specifically addressed, expertise in fungal diagnostics is equally important to optimal AFS.

Recommendation: We recommend that centers that frequently manage patients with invasive fungal disease have access to timely conventional and non-culture-based diagnostic testing for Candida and Aspergillus species.

Early and accurate diagnosis of IFD is one of the most important factors influencing outcomes of fungal diseases and appropriate prescribing of antifungal therapy. Over the last 2 decades, non-culture-based tests (NCBTs) such as galactomannan, Aspergillus polymerase chain reaction (PCR), mannan, anti-mannan antibody, and (1→3)-β-D-glucan (BDG) have become essential tools for early detection of IFD in both neutropenic and nonneutropenic patients (Table 1). These tests have been incorporated in diagnostic criteria for IFD that can be managed through diagnostic-driven pathways in some centers that rely on early detection of biomarkers plus radiological or clinical signs (CT imaging findings, persistent fever, localizing symptoms) as a trigger for starting antifungal therapy [56, 57].

The high negative predictive values (NPVs) of NCBTs are valuable for de-escalation of empiric antifungal therapy, but require careful interpretation by clinicians with expertise in managing IFDs [68–71]. Although routine discontinuation of antifungal agents in patients with negative NCBTs has not been widely endorsed in treatment guidelines to date [57, 72, 73], negative tests provide useful microbiological evidence as part of a broader clinical and/or radiological assessment that could support discontinuation of empirical antifungal therapy. However, the performance of NCBTs can vary depending on the host, type of underlying immunosuppression, test sample (ie, serum vs bronchoalveolar lavage fluid), and concomitant medications or treatments [57, 74–76].

Diagnostic stewardship is becoming an important component of any anti-infective stewardship program. Judicious use of NCBTs requires the ordering practitioner to consider the pretest probability of IFD in the presenting patient. Disease likelihood relies on multiple factors, with the most common being the underlying disease risk factors for IFD, persistent fever on broad-spectrum antibiotic therapy, and the presence of any signs or symptoms consistent with IFD. The pretest probability for IFD in an individual patient may be estimated with institutionally validated prognostic risk models or risk scores, such as those reported for invasive candidiasis [77–80] and invasive aspergillosis [81]. However, such risk scores often must be adapted and validated to the local clinical context before broad institutional use [82]. Thus, it is more common in many medical centers to generally classify patients to be at high, low, or intermediate risk for developing IFD. Policies for diagnostic stewardship should be developed in conjunction with institutional colleagues from clinical microbiology laboratories and ID, particularly those with expertise in medical mycology.

As a general rule, NCBTs for IFDs have limited clinical utility if the pretest probability of IFD falls below 10% [83] or if a positive test does not increase the probability of disease above a threshold that would be considered for prophylaxis or therapy (ie, >15%–30%). Given that the global rate of invasive candidiasis in many ICUs ranges between 1.8% and 7.8% [80] and rates of probable or proven mold disease in the total hematology population are typically <3% [81], special attention should be paid by AFS programs to the use of NCBTs for screening in asymptomatic patients. Currently approved tests that measure galactomannan antigen and BDG are subject to frequent false-positive results and could trigger unnecessary antifungal therapy or diagnostic procedures if frequently used in patient populations with a low pretest probability of IFD. For example, Duarte and colleagues [84] reported that routine galactomannan screening in patients receiving posaconazole prophylaxis was more frequently associated with a false-positive result (13.8%) rather than true disease, resulting in increased unnecessary diagnostic studies (chest CT) in asymptomatic patients.

A number of rapid diagnostic tests for invasive candidiasis, including matrix-assisted laser desorption/ionization–time of flight spectrometry, multiplex PCR, peptide nucleic acid fluorescent in situ hybridization, and T2 magnetic resonance detection panels, have been introduced over the last 2 decades (Table 2). The clinical impact of these rapid tests, particularly their ability to reduce time to appropriate antifungal therapy or reduction in antifungal usage, has been consistently shown to be improved when results are reported in coordination with AFS activities [85–90]. Although they are still being investigated, non-culture-based biomarkers hold promise for early diagnosis of mucormycosis [91, 92].

CORE ELEMENT 4: EDUCATION AND PRACTICAL TRAINING

Recommendation: We recommend the development of targeted educational programs as part of a multifaceted antifungal stewardship program to address knowledge gaps in the interpretation of microbiology laboratory results, differentiation of colonization vs infection, indications for prophylaxis vs empiric therapy, and antifungal therapy dosing and monitoring.

Education alone is not considered to be an effective AFS intervention [12]. However, several studies have documented frequent gaps in prescribers’ knowledge with respect to differentiating fungal colonization from disease and indications for prophylaxis vs empirical antifungal treatment [102].

Numerous studies have surveyed inappropriate antifungal use in hospitals and have shown significant gaps in the knowledge of appropriate antifungal prescribing. For example, Nivoix et al found that 40% of antifungal use in a French hospital was inappropriate with respect to either indication, dosage, risk of drug–drug interactions, or antifungal susceptibility results [7]. The most common reasons for inappropriate prescribing were use of prophylaxis for nonapproved indications, lack of weight-based dosing of fluconazole, and lack of dose reduction according to renal function. In a retrospective cohort study of 305 hospitalized patients at 4 US medical centers, Jacobs and colleagues found that roughly half of patients with asymptomatic candiduria received antifungal therapy despite data suggesting the value of no treatment [9]. A recent PK point-prevalence study reported that antifungal agents, particularly fluconazole, were routinely underdosed in one-third of patients with sepsis [103], a previously reported independent risk factor for patient death [104]. The finding of relatively high prevalence of fluconazole underdosing is noteworthy as many AFS programs do not monitor fluconazole prescribing because of the relatively low cost of this medication [17, 20, 105, 106], even though it is still the most widely prescribed antifungal agent (often inappropriately for candiduria or yeast in respiratory specimens). The predictive value of Candida in the urine or respiratory secretions for invasive candidiasis is very low, even in severely neutropenic patients [107, 108]. Misuse of fluconazole may profoundly influence the epidemiology of Candida bloodstream infections and is associated with increased rates of antifungal resistance [109, 110].

Valerio et al evaluated prescriber knowledge of IFD diagnosis and treatment and identified several key knowledge gaps in the areas of interpretation of microbiological results, antifungal selection, and dosing [102]. Knowledge gaps identified in the prescriber survey were then used to design an interactive training strategy that was incorporated into a multifaceted AFS program with patient bedside interventions [22]. Hence, education plays an important complementary role with other AFS initiatives to improve appropriateness of antifungal prescribing.

Recent trends in integrating stewardship principles into the curricula of a variety of healthcare and postgraduate training programs is encouraging and essential to improving the knowledge of our workforce; these programs should also include elements of AFS.

CORE ELEMENT 5: OTHER ACTIONS AIMING AT RESPONSIBLE ANTIMICROBIAL USE

Recommendation: We recommend, whenever possible, that infectious diseases consultation be performed for patients with invasive fungal diseases such as fungemia, invasive aspergillosis, mucormycosis, and cryptococcal meningitis.

The complexity of patients who acquire IFDs is well recognized, and mortality rates associated with these infections are among the highest of all infectious diseases. Several recent studies have demonstrated the impact of ID consultation on outcomes in patients with candidemia and cryptococcosis and have shown improvement in the performance of quality measures and/or lower mortality [111–119]. This is especially important in hematology units with high prevalence of resistant fungi or presence of non-Candida opportunistic yeasts as causes of fungemia, where general guideline-based recommendations for preemptive antifungal use might not be optimal [120]. Data are lacking for other individual IFDs, but ID consultation for these other infections may be embedded in a comprehensive approach to care [121], and specialized infection management will likely be critical. While face-to-face consultation is commonplace in the US and may be preferable, it is not always readily available in all circumstances and resource-limited settings. In these situations, it may be especially important to implement other pathways and stewardship interventions to optimize care [42, 43, 122, 123]. A recent study evaluated published data on outcomes of telemedicine vs in-person ID consultation, but the variety of methods and outcomes used in the primary literature hampered meta-analysis [123]. This is an evolving area deserving of further study.

Recommendation: We recommend the development of institutional care pathways or treatment bundles as well as guidelines to improve the probability that diagnostic and therapeutic interventions for invasive fungal disease are delivered in a timely and logical sequence to maximize patient outcomes and provider education.

Prescriber education and the development of local guidelines are often the first steps for implementing AFS programs [44]. National or international guidelines are available for treatment and prevention of common IFDs and provide expert evaluation of published evidence concerning the best diagnostic and therapeutic approaches. Several noncontrolled studies have suggested that patients are more likely to have early consultation by an ID specialist, earlier source control, timely diagnostic examinations, and appropriate antifungal therapy selection and treatment duration when prescribers adhere to treatment guidelines during the management of invasive candidiasis [112, 116, 124–128]. However, the adherence rates to treatment guidelines may be relatively low outside large-high volume tertiary care or university-affiliated medical centers [129, 130]. More recently, quality scoring systems have been proposed to provide metrics of prescriber adherence to international guidelines for invasive candidiasis [131], invasive aspergillosis [132], cryptococcosis [133], and mucormycosis [134], although it is still unknown whether such quality scores are associated with improved patient outcomes.

Many decisions involved in the management of IFD must be instituted in a specific sequence over a short time frame to have maximal clinical impact. Clinical care pathways or treatment bundles are another useful strategy to ensure that critical diagnostic tests and source control procedures are performed in a timely fashion when antifungal therapy is started, in order to maximize treatment effectiveness. These bundles must be available at the point of care, whether embedded in computer decision support systems or linked to expert prescribers such as ID physicians or clinical pharmacists, in order to facilitate earlier consultation for questions concerning optimal drug selection, dosing, or management of drug interactions in medically complex or critically ill patients. Even without ID consultation, treatment bundles for candidemia developed and implemented by members of the AMS team have been shown to improve performance of elements such as antifungal therapy utilization and duration, ophthalmological examination, and removal of central venous catheters [135]. Algorithms have been proposed for preemptively treating cryptococcal infection on the basis of cryptococcal antigen screening in asymptomatic patients with newly diagnosed human immunodeficiency virus in resource-limited areas [136–138]. While the optimal antifungal therapy has yet to be defined for this situation, it demonstrates another way to facilitate prompt diagnosis and treatment of a serious fungal infection in a high-risk population where there is a lack of readily available ID consultants.

Most treatment bundles are not an exhaustive list of precise protocols, but rather a set of 3–5 steps that local experts believe are critical to execute at the time antifungal therapy has started and while monitoring response to treatment. Examples of typical bundle elements for invasive candidiasis and invasive aspergillosis are shown in Table 3.

Takesue and colleagues developed a 9-component management bundle for invasive candidiasis based on Infectious Diseases Society of America (IDSA) guidelines that focused on 3 elements at the start of antifungal therapy and 6 elements for follow-up after antifungal therapy was started [126]. The bundle was implemented in 11 regional medical centers and was used to manage 648 nonneutropenic patients with candidemia. The investigators found a significant difference in clinical outcomes between patients with and without bundle compliance (92.9% vs 75.8%, P = .011). Independent elements of the bundle that contributed to clinical success of candidemia treatment included central venous catheter removal within 24 hours after confirmation of a positive blood culture, assessment of the clinical efficacy after 3–5 days of antifungal therapy to consider the necessity of alternative treatments, and continuation of antifungals at least 2 weeks after clearance of Candida from the bloodstream. Vena and colleagues demonstrated that a more exhaustive bundled approach for patients with candidemia was associated with lower 14- and 30-day mortality [139]. Admittedly, there may be some disagreement regarding the merits of individual aspects of these treatment bundles [144–148], but the data suggest that, overall, treatment bundles can be a very effective approach toward improving antifungal prescribing and improving patient outcomes.

Recommendation: Ongoing interventions such as “handshake stewardship rounds” or postprescription review and feedback should be considered an essential part of a comprehensive antifungal stewardship approach.

Expert postprescription review and feedback (PPRF) has been identified as the most valuable intervention for improving antifungal prescribing and reducing antifungal consumption and costs [12, 106]. PPRF focuses on the identification of target patient populations when pathogens are identified or a target (typically high-cost) antifungal is prescribed. These triggers lead to an evaluation of the IFD management by one member of the AFS team (eg, ID physician, pharmacist, and/or clinical microbiologist) who can advise the prescriber about patient-specific clinical and microbiological issues to improve care.

Recent studies have reported the benefit of newer interventions such as “handshake stewardship rounds” that engage providers in an ongoing discussion about rational antimicrobial prescribing. In a children’s hospital setting, this approach was associated with a 12.1% decrease in antifungal days of therapy (DOT) per 1000 patient-days (131 to 109 DOT/1000 patient-days) [149]. Similarly, academic detailing rounds have been reported to increase concordance with AMS recommendations even in the challenging setting of solid organ transplantation [150]. This conceptually simple, yet time- and resource-intensive type of stewardship intervention is recognized as an effective and sustainable stewardship practice and is worthy of further consideration [151]. These and other AFS activities are outlined in Table 4.

Other methods such as preauthorization may be used, but in at least 2 recent studies have been shown to be less effective for AMS [153, 154]. PPRF was associated with more pharmacist interactions with clinicians, identification of more instances of inappropriate antimicrobial use, and improved de-escalation than preauthorization. Strict preauthorization may also be challenging to implement owing to the difficulty in ensuring a thorough and timely review of antimicrobial utilization by a member of the AMS team prior to the first dose [154].

Recommendation: We recommend that facilities evaluate the quality of antifungal prescribing on a systematic basis, and use data-driven strategies to further optimize antifungal stewardship interventions.

Data-driven approaches have been shown to aid stewardship programs in optimizing antimicrobial use. Conducting medication-utilization evaluations or disease state–based evaluations can be an important part of this work, as these illuminate potential areas for improvement [155]. Examples of performance measures and outcomes that could be assessed are shown in Table 5. Several tools have also been developed to help AFS teams in evaluating antifungal use and quality of care for patients with fungal infections [3, 131–134]. These tools have not yet been widely utilized, but are a promising area to support data-driven AFS efforts.

Recommendation: Additional research is needed to develop and evaluate new tools to facilitate antifungal stewardship, so that interventions have maximal impact and require minimal resources.

In the future, additional innovative methods for AFS may be employed. These include the use of artificial intelligence to better identify opportunities for optimizing fungal infection diagnosis and antifungal prescribing. One recent study described such an approach, which used machine learning algorithms to identify invasive fungal pneumonia through review of CT scan reports from patients with hematologic malignancies [156]. Medical record reviews were subsequently performed to verify proven/probable invasive mold disease and identify potential areas of process improvement for the hospital, such as selection and administration of appropriate antifungal prophylaxis, attainment of therapeutic concentrations of prophylactic antifungals, and delays in performance of diagnostic testing. While there are several limitations to this approach (eg, its independent impact on AFS and the sensitivity, specificity, positive predictive value [PPV], and NPV of natural language in different types of high-risk patients where radiologic findings might be due to several other causes such as extramedullary leukemia or coinfection), this is an intriguing area where additional development could potentially result in new tools that will help facilitate AFS activities.

In addition, novel methods such as time-series analyses and linear regression have been used to identify periods of over- and underutilization of antibiotics within a given hospital, allowing for identification of “antimicrobial use outbreaks” [157]. These methods effectively and necessarily control for seasonality and baseline expected antimicrobial utilization associated with a certain level of patient acuity within a facility, and similar approaches have been effectively utilized by infection prevention programs for many years. A pattern of unexpected antimicrobial and/or antifungal use can be identified and investigated more rapidly, adding efficiency to the work of the stewardship team. These methods could be potentially applied to AFS as a way of generating more meaningful internal data for action by stewards.

CORE ELEMENT 6: MONITORING AND SURVEILLANCE

Recommendation: We recommend that all centers that manage patients with invasive fungal disease establish or adapt local surveillance systems for fungal infections to support antifungal stewardship program initiatives.

Adherence to treatment guidelines is enhanced when evidence-based treatment recommendations are adapted to local circumstances, epidemiology, and care pathways with input from local expert clinicians [44]. This requires institutions to have adequate surveillance systems in place to measure the IFD burden and epidemiological trends that help direct stewardship strategies. Continuous surveillance in hospitals is also essential for detecting and containing emerging threats such as multidrug-resistant Candida auris [158, 159].

The key elements of this surveillance should include (1) standardized case definitions for IFD [160]; (2) defined patient populations identified for continuous monitoring; (3) identification of cultured fungal pathogens to the species level whenever possible; (4) established mechanisms for real-time reporting, analyzing, and disseminating data to prescribers; and (5) incentives for conducting surveillance [158].

Surveillance of IFD is inherently challenging as traditional culture-based methods for case diagnosis have limited sensitivity, so many patients treated with systemic antifungals may be missed. An increasingly larger percentage of cases are diagnosed by NCBTs. Distinguishing colonization from infection can be difficult for Candida species, and in the case of Aspergillus species may require histopathological evidence of tissue or organ invasion by fungi [160], which is often difficult in critically ill or severely pancytopenic patients. Even in the era of more sensitive fungal biomarkers, many clinically significant IFDs are missed [161]. As many immunocompromised patients with diagnostic imaging features of invasive mold infection on chest CT scan receive empirical antifungal therapy in the absence of positive cultures or NCBT results, such cases may not be detected in a routine AFS monitoring program.

Recommendation: We recommend that centers routinely managing invasive fungal diseases have access to timely antifungal susceptibility testing.

Antifungal susceptibility testing is recommended in both US and European treatment guidelines during the management of invasive candidiasis to guide treatment selection and support stepdown therapy to oral triazoles [140, 141], especially in nonneutropenic patients. Its contribution is less clear in high-risk neutropenic patients with cancer where azole-resistant species are quite common [162, 163]. The role of in vitro susceptibility testing in the management of invasive aspergillosis and other molds is less well established [142,143,164], but is likely to increase in the near future with reports of increasing triazole resistance in Aspergillus species, the emergence of resistant non-Aspergillus molds, and the potential future approval of new antifungal classes [11, 165]. The Clinical and Laboratory Standards Institute and the European Committee on Antimicrobial Susceptibility Testing have developed standardized microdilution broth antifungal susceptibility testing methods with associated clinical breakpoints for most common fungal species and frequently prescribed antifungals [166, 167]. A number of other commercial testing methods (eg, agar diffusion tests [disk and gradient strips], commercial microbroth dilution tests, or the semiautomated VITEK system [bioMérieux, Marcy l’Etoile, France]) are available. All of these tests can reliably detect triazole and echinocandin resistance; however, local validation and expertise in antifungal susceptibility testing are important for interpretation [168].

An emerging area of research in this regard involves identifying predictors of antifungal resistance among at-risk populations [169–173]. Further development and validation of predictive models may aid in AFS efforts to optimize antifungal selection and utilization in these populations where antifungal resistance is more commonly encountered.

Recommendation: Although there are limited data evaluating their utility for antifungal stewardship, we recommend that centers that perform routine antifungal susceptibility testing develop cumulative antifungal susceptibility reports.

Susceptibility data can be used to generate cumulative antimicrobial susceptibility reports (CASRs) to serve as an epidemiological surveillance tool and to assess the effectiveness of different stewardship interventions. Antibacterial CASRs help prescribers select effective therapy when culture results are pending and aid ASPs in informing and updating local guidelines for empirical treatment of common infection syndromes including recommendations for prophylaxis [152]. CASRs also provide the rationale for antimicrobial formulary selection, surveying local resistance and benchmarking for collateral impact of antibiotic use in the institution (eg, incidence of fluoroquinolone or carbapenem resistance), as well as identifying targets for stewardship interventions.

Few hospitals currently report fungal susceptibilities in CASRs, and unlike antibacterial agents [174], no specific standards have been proposed on how to construct or analyze such reports for antifungals. Nevertheless, a number of studies have demonstrated correlations between antifungal usage and the emergence of resistance in Candida species [173, 175, 176]. Current guidelines for antibiotic CASRs recommend testing only diagnostic (not surveillance) first isolates [174]. Additional analysis of follow-up cultures may be necessary to fully understand the presence of resistant organisms within a facility [169, 177]. For Aspergillus species, surveillance of triazole resistance may also require environmental surveillance; expert recommendations have discouraged empiric triazole use for Aspergillus in high-risk patients when environmental triazole resistance rates exceed 10% [178].

Antifungal CASRs also provide useful year-to-year epidemiological data that are important for analyzing susceptibility trends and evaluating the utility of new antifungals currently in development with unique spectra of activity. Given the small number of isolates at some centers, it is likely that susceptibility data from multiple years will need to be combined to provide a reliable picture of susceptibility rates. Shifts in patient mix or factors predisposing to IFDs among a facility’s population may also impact susceptibility over time and should be considered [172, 179].

Recommendation: We recommend that antifungal stewardship promote rational diagnostic testing and that the results of both fungal culture and non-culture-based tests are communicated to antifungal stewardship teams to facilitate “real-time” interventions.

Generally, the high NPV of BDG, mannan–anti-mannan, or T2 magnetic resonance results should support decisions to withhold antifungal therapy in most patients with an estimated pretest prevalence of invasive candidiasis ranging from 0.4% to 10% [180]. However, the routine use of such tests in patients already at low risk for invasive candidiasis (ie, <5%) minimally reduces the already low probability of infection and is not cost-effective [181]. On the other hand, in some subsets of critically ill patients with intra-abdominal candidiasis, the NPV threshold of NCBT may not be sufficiently low (ie, ~ 6% of infection) to withhold antifungal therapy in a severely ill patient without an alternative diagnosis [180]. However, at least one group integrated both the NPV of the BDG test with a designated “champion for stewardship” within an ICU to reduce both antifungal consumption and patient mortality [182]. This strategy reduced inappropriate initiation of antifungal therapy by 90%. These types of biomarker-based strategies may work best within a team concept with multilayer controls.

Positive NCBTs must be carefully interpreted and can have unintended consequences of driving unnecessary antifungal prescribing. Specifically, positive NCBTs in patients with a very low pretest probability of disease are associated with a low PPV and are probably insufficient to justify treatment. A positive NCBT is most useful in patient populations with a reasonable baseline probability of disease (ie, 5%–15%) where a positive result would significantly upgrade infection likelihood and the justification for starting antifungal therapy [180]. Discrepant positive NCBT results in patients with negative cultures can be particularly challenging to interpret in some high-risk populations and can drive overprescription of antifungals and spurious reporting of hospital infection rates [180]. Thus, expertise in fungal diagnostics is required to understand both the strengths and limitations of NCBTs, and how the results should be interpreted.

Recommendation: We recommend that all patients have their medication record screened by a clinical pharmacist or clinician to carefully assess for antifungal drug interactions. This should also be performed when starting and stopping concomitant medications.

Drug–drug interactions are frequently encountered in patients requiring antifungal agents, and have been reported in approximately 88% of hospitalizations where mold-active triazoles were administered [183]. These interactions have potentially serious consequences including increased risk of QTc prolongation/cardiac arrhythmias, seizures, leukopenia or nephrotoxicity, and interference with the metabolism of chemotherapy, anesthetic agents, or cardiovascular medications as well as subtherapeutic antifungal concentrations. The complexity of patients commonly requiring antifungal therapy increases the likelihood of polypharmacy and the potential of such interactions occurring.

Frequently, severe drug–drug interactions may be identified without clear recommendations or medical guidance. In these cases, clinical expertise in managing IFD and drug–drug interactions in consultation with primary teams is important in developing an individualized strategy that minimizes risks to the patient while maintaining effective therapeutic regimens—for example, alternative prophylaxis regimen, TDM, or reduction of immunosuppressive drug dosage, such as with voriconazole and sirolimus.

Recommendation: We recommend that centers routinely managing patients with invasive fungal disease have access to timely therapeutic drug monitoring for triazole antifungal agents.

Triazole antifungals are the most frequently prescribed class of antifungal agents and subject to considerable intra-and interpatient PK variability [184], potentially putting patients at risk for subtherapeutic or toxic drug exposures [185–187]. TDM is the most direct way to identify patients who are at increased risk for treatment failure or toxicity due to altered PK. The availability of in-house TDM has been reported to shorten time to drug concentration results and attainment of therapeutic drug concentrations [187, 188]. However, the resources and expertise for in-house analysis may not be available in all centers or may only be available as a send-out test to an outside reference laboratory with associated delay before results are available. As a result, the role and application of TDM will vary from center to center.

TDM should be considered for patient populations who are likely to have unpredictable oral drug absorption if receiving oral triazoles, such as those with severe mucositis with diarrhea, vomiting, or who may have altered antifungal PK such as pediatric, obese, or critically ill patients with altered organ function or extracorporeal circuits including dialysis or extracorporeal membrane oxygenation [103, 189]. TDM has been specifically recommended for the majority of patients receiving voriconazole, posaconazole, itraconazole, and flucytosine [140, 184, 188]. However, even for fluconazole, subtherapeutic exposures have been observed in one-third of critically ill patients [10]; patients on high-volume renal replacement therapy [10, 103, 190] or pediatric patients with febrile neutropenia [191] may be particularly susceptible to lower exposures. Isavuconazole is a newer triazole and, in analysis of data from primary treatment of invasive aspergillosis (SECURE) trial and real world experience at one diagnostic laboratory, appeared to have relatively low inter- and intrapatient variability [192, 193]. Others have reported moderate variability in concentrations achieved in certain populations such as solid organ transplant recipients [194, 195]. Emerging data on echinocandins and other antifungal agents in special populations may also support broader TDM requirements in certain populations [196–198].

Other scenarios where TDM may provide useful information include patients with suspected drug concentration–related toxicities (ie, central nervous system disturbance or hypokalemia with hypertension); intravenous to oral transitioning of therapy in patients with documented IFD; during the management of drug–drug interactions; or in patients with breakthrough IFD [184, 199]. In the latter case TDM helps establish whether breakthrough infection occurred in the presence of “therapeutic” triazole concentrations or may be attributed to inadequate drug exposures [200]. Decisions about the need to use TDM for particular antifungals may also fall under the umbrella of diagnostic stewardship and require consideration of local factors as well [93, 201]. Inherent to the success of TDM is a pharmacokinetically sound approach to the adjustment of dosages. This may be challenging in drugs with nonlinear, saturation, Michelis–Menten type PK, such as voriconazole. The AFS should include or have readily available the PK expertise to manage pharmacokinetically complex antifungal agents.

CORE ELEMENT 7: REPORTING AND FEEDBACK

Recommendation: All facilities should have a mechanism to track antifungal drug use.

Reporting and feedback can be one of the most powerful tools to drive change in AFS programs. The first and most widely used metric for any AMS is drug use. Available metrics for measuring antifungal drug use are largely the same as those available for antibacterial agents and will be familiar to the AMS team [202]. In general, measures of antifungal drug use that expand beyond expenditures and represent actual patient drug exposure are preferred. The 2 primary metrics used for this are DOT [203] and defined daily dose (DDD) [204]. While the former is the preferred metric in the US and the standard used for national inpatient antibiotic use measurement, the latter is widely used in Europe. There are advantages and disadvantages to each, related to the ability of each technique to be used widely (including in pediatric populations and in patients with significant hepatic and/or renal function) as well as to differences in collection method; DOT requires access to data from an electronic medication administration record, whereas DDD can be calculated from a variety of different data sources and approximate an average daily dose an adult patient would receive. A detailed review of these metrics including their advantages and disadvantages in special populations has been described elsewhere. These concepts apply to both antibacterial and antifungal agents [205].

To account for differences in patient volumes, a normalizing denominator such as patient-days, patient admissions, days present (a novel method described by the US CDC), or inhabitants for a given geographic area is typically applied [203, 206, 207]. The denominators can be used with either estimate of total drug use and have even been applied to normalize overall treatment costs (eg, antifungal cost per patient day). Each of these provides a way to compare data based on patient volumes and can readily be calculated at the level of the entire facility for a specific unit, ward, or type of ward within the facility.

However, there are certain factors that make quantifying and reporting on the quantity of antifungal drug use distinctly different than that of antibacterial use. First, the overall quantity of antifungal drug utilization at the facility level is on a different level of magnitude than that of antibacterial use. Interpretation of antibacterial use is aided by the sheer large quantity that is observed. For example, in US hospitals, approximately 50% of all hospitalized patients will receive some antibacterial agent while hospitalized [208]. As a result, even the smallest of facilities will be able to measure thousands of antimicrobial administrations each day. In contrast, <3% of all US inpatients will receive an antifungal agent during admission [6], meaning that use in some hospitals may be limited to very small patient populations, making aggregate summary data of overall antifungal use difficult to interpret. In fact, for the smallest of hospitals, variations in antifungal use can be attributed to a single patient with a suspected or confirmed fungal infection. These fluctuations can make stewardship interventions targeting antifungal drug use difficult to measure.

Conversely, in other cases, significant use of antifungal agents can obscure some use trends that might be of interest. This includes oncology units, where certain patient populations receiving antifungal prophylaxis may make it appear that there is 100% antifungal coverage (demonstrated as 1000 or >1000 DOT/1000 patient-days). When such a large proportion of patients are receiving continuous antifungal therapy, it can be difficult for data trends to emerge such as potentially unnecessary combination antifungal therapy warranting stewardship intervention.

Recommendation: Benchmarking antifungal use can aid in antifungal stewardship work.

Given the variation in antifungal drug use that can be seen based on hospital size and patient population, finding similar hospitals with which to compare data can be one of the best ways to begin identifying targets for AFS interventions based on consumption data. However, finding a source for benchmarking can be difficult. Both the US and Europe have mechanisms to benchmark and compare antifungal drug use.

In the US, the NHSN, administered by the CDC, has developed risk-adjusted metrics for antimicrobial use. In the 2019 update of these methods, antifungal agents targeting invasive candidiasis were included for the first time, permitting hospitals to compare antifungal use in adult and pediatric medical, surgical, and combined medical and surgical wards and ICUs as well as adult step-down and hematology/oncology units [203, 209]. Adult antifungal use in DOT per 1000 days present is risk-adjusted for several facility-level factors, including location type, facility type, total number of hospital as well as ICU beds, and average length of hospital stay. Facility use is reported as a ratio of the observed DOT compared to the risk-adjusted expected DOT. The reported ratio is referred to as the standardized antibiotic administration ratio (SAAR), with values >1 representing more use than predicted. A SAAR was also recently developed for neonatal fluconazole use and can be used for neonatal critical care units and step-down nurseries [209].

These larger national and regional comparisons are relatively new, and not all facilities are able to report the data needed for these benchmark reports. As a result, more informal benchmarking groups including provincial, state, and regional stewardship collaboratives that are willing to share data have also formed; this collaboration can also happen with select drug purchasing groups. While there are no specific standards that have been developed for these informal collaboratives, there are some key principles that should be followed. First, data should be obtained from the same source: Even when using a metric such as a DDD, if it is calculated by some partners using purchasing data and others using administration data, there may be a significant difference in what is observed due to the data source alone. There are several reasons why purchasing data do not reflect actual patient exposure owing to the practices and complexities of health system drug acquisition. Second, comparator hospitals with similar patient populations should be included, and this is especially true for facilities with oncology and solid organ transplant populations. Finally, data collection practices at the hospitals should be similar. There may be variability in results due to inclusion of certain areas in the hospital such as perioperative areas, where in some hospitals antimicrobial prophylaxis is recorded in the operating room (possibly in a separate electronic record) and in others attributed to the inpatient ward. Inclusion of alternate routes of administration can also influence results and should be consistent across hospitals. For example, in one stewardship collaborative, great variability was observed in overall antifungal use that was ultimately attributed to some facilities only reporting data regarding oral nystatin administration (unpublished data, Duke Antimicrobial Stewardship Outreach Network). Therefore, as with all benchmarking data, these data should be interpreted with caution to ensure that accurate and fair comparisons are being made.

Recommendation: Antifungal stewardship programs should ideally assess patient-level outcomes where possible.

In addition to quantifying antifungal drug use, stewardship programs should employ measures that assess the overall effectiveness of interventions. As a primary goal of any stewardship program, including those targeting antifungal use, appropriateness of prescriptions remains a metric of much interest. It has proven difficult to best define appropriate antimicrobial use [210, 211]. Consensus opinions have concluded that it is best to assess appropriateness of use by comparing patterns of use with locally accepted guidelines for best practices that are adjusted and refined to local patient prescribing practices and epidemiology of infection [202, 210]. Just as important may be examination of patient outcomes such as mortality, via autopsy studies and/or medical record reviews to assess for undiagnosed IFDs [212–214]. These endeavors may help to identify areas where antifungals have been underutilized or employed too late in the disease process, and may generate another actionable item for quality improvement activities as part of the AFS program.

Other indicators for measuring antifungal drug use that may be useful to AFS programs include the process measures of how often planned stewardship interventions are performed. Examples of these are described above for implementation of candidemia bundles [124] and can also include conversion from intravenous to oral therapies, the number of cases reviewed, the number of guidelines developed, and so forth [211]. In fact, measuring that a process was actually implemented is vitally important to measuring the impact of a program and should not be overlooked when planning stewardship interventions [93, 202, 205, 215].

There is a desire to capture more patient-centered metrics where possible. At present, data supporting AFS program impact on overall mortality, hospital length of stay, and ICU length of stay are largely limited to single-center experiences with variable outcomes [44, 93]. These may be challenging targets to influence with stewardship interventions given the complexity of underlying disease and the various factors that contribute to healthcare resource utilization. The prominent role of antifungal therapy in prophylaxis at many institutions provides the ability to track some novel outcomes such as infection-free prophylaxis courses and balancing measures such as breakthrough-resistant infections. These are important program outcomes that should be considered when defining AFS-related metrics [44, 106].

Recommendation: All antifungal stewardship programs should have a mechanism for direct data feedback to prescribers.

The CDC Core Elements of Stewardship promote using stewardship data to drive change by ensuring it is widely disseminated [15]. This is also vitally important to AFS efforts. As is the case with AMS, direct feedback to front-line prescribers either at the individual, service, or unit level has been described as a key factor for success for many antifungal-based stewardship interventions [3, 93, 216]. A plan to disseminate data to prescribers should be a part of any AFS program. These data may need to be different from information used to report stewardship program interventions to leadership, as it should be in a format to allow prescribers to easily interpret and apply to local practices, whereas leadership often receives data regarding AFS initiatives in aggregate.

CONCLUSIONS

This document addresses how the global consensus of core elements for AMS can be applied to antifungal therapy and provides specific recommendations for developing coordinated interventions to measure and improve appropriate use of antifungal agents. Stewardship and its formal elements and principles attempt to put structure around utilization of antimicrobial agents, and it is clear that this effort can and should extend to antifungal agents and the prevention and management of IFDs. Given the high rates of inappropriate antifungal use in many institutions, the development of AFS programs provides a foundation for improved communication, diagnosis, and management of IFDs, while optimizing patient outcomes and increasing cost-effectiveness. Many of these recommendations are based on global utilization, but adoption of these principles will require some tailoring at the local level based on the differences between healthcare systems and practices. Although many intriguing questions specifically relating to AFS remain (Table 6), the practice of AFS is expanding and its continued growth will be necessary for us to optimize our care of patients at risk of or afflicted with IFDs.

Notes

Acknowledgments. D. P. K. acknowledges the Texas 4000 Distinguished Professorship for Cancer Research and the National Cancer Institute (National Institutes of Health) Cancer Center (CORE support grant number 16672).

Supplement sponsorship. This supplement is sponsored by the Mycoses Study Group Education and Research Center (MSGERC).

Potential conflicts of interest. M. D. J. reports personal fees from Astellas, Paratek, Shionogi, Cidara and UpToDate, and grants from Astellas, Scynexis, Charles River Laboratories, and Merck & Co, outside the submitted work. R. E. L. reports grants from Merck, and personal fees from Gilead and Cidara Therapeutics, outside the submitted work. E. S. D. A. reports personal fees from The Joint Commission Resources and UptoDate, outside the submitted work. L. O.-Z. reports personal fees from Astellas, Cidara, Gilead, Pfizer, F2G, Mayne, Stendhal, and Biotoscana, and grants from Astellas, Cidara, Scynexis, Real Time, and Amplyx, outside the submitted work. T. Z. reports personal fees from Pfizer, outside the submitted work. G. R. T. reports grants from Astellas, Amplyx, Cidara, Mayne, Scynexis, and F2G, and other from Astellas, Amplyx, Cidara, Mayne, Scynexis, Pfizer, and F2G, during the conduct of the study. D. R. A. reports other from Amplyx, Fedora, Roche, and Matinas, and grants from Amplyx, Fedora, and Merck, outside the submitted work. T. J. W. has received grants for experimental and clinical antimicrobial pharmacology and therapeutics to his institution from Allergan, Amplyx, Astellas, Lediant, The Medicines Company, Merck, Scynexis, and Tetraphase, and has served as consultant to Amplyx, Astellas, Allergan, ContraFect, Gilead, Lediant, Medicines Company, Merck, Methylgene, Pfizer, and Scynexis, outside the submitted work. P. G. P. reports grants from Merck, Astellas, Scynexis, IMMY, Cidara, and Amplyx, and personal fees from Cidara and Amplyx, outside the submitted work. O. A. C. is supported by the German Federal Ministry of Research and Education; is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany’s Excellence Strategy–CECAD, EXC 2030–390661388; has received research grants from Actelion, Amplyx, Astellas, Basilea, Cidara, Da Volterra, F2G, Gilead, Janssen Pharmaceuticals, The Medicines Company, MedPace, Melinta Therapeutics, Merck/MSD, Pfizer, and Scynexis; is a consultant to Actelion, Allecra Therapeutics, Amplyx, Astellas, Basilea, Biosys UK Limited, Cidara, Da Volterra, Entasis, F2G, Gilead, Matinas, MedPace, Menarini Ricerche, Roche Diagnostics, Merck/MSD, Nabriva Therapeutics, Octapharma, Paratek Pharmaceuticals, Pfizer, PSI, Rempex, Scynexis, Seres Therapeutics, Tetraphase, and Vical; and has received lecture honoraria from Astellas, Basilea, Gilead, Grupo Biotoscana, Merck/MSD, and Pfizer. J. R. P. reports grants from Astellas, Pfizer, Minnetronix, and Amplyx; advisory board honoraria from Merck, F2G, Ampili, and Matinas; and advisory board/consulting honoraria from Scynexis, outside the submitted work. D. P. K. reports research support from Astellas Pharma and honoraria for lectures from Merck & Co, Gilead, and United Medical; has served as a consultant for Astellas Pharma, Cidara, Amplyx, Astellas, Pulmocide, and Mayne; and is a member of the data review committee of Cidara.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.