Ananda-Rajah, Michelle R.a; Slavin, Monica A.b,c; Thursky, Karin T.b,c
Antimicrobial stewardship (AMS) has largely focussed on the judicious use of antibiotics while antifungal agents have received less attention. However, it is likely that the practice of antifungal stewardship (AFS) has been commonplace at many institutions for years, principally because of the high cost of antifungal drugs and the specialized patients to whom they apply. Antifungal agents are usually on restricted formularies in hospitals, requiring the input of experts such as infectious diseases physicians and pharmacists who are knowledgeable of local fungal epidemiology, susceptibility patterns and current clinical literature to guide prescribing. AMS has been defined as the ‘ongoing effort by a healthcare institution to optimise antimicrobial use in order to improve patient outcomes, ensure cost effective therapy and reduce adverse sequelae’ . Inappropriate antibiotic use is associated with collateral damage, namely the emergence of bacterial resistance, adding to the burden of hospital acquired infection, patient morbidity, mortality and cost [2,3]. As a result, there has been a call to arms in recent years promoting the institution and strengthening of hospital AMS programmes . However, although these programmes broadly include antifungal agents, data on optimizing rather than auditing their use in clinical settings is scarce .
Similar to the diminishing pipeline of new antibiotic choices in the face of escalating global resistance, novel antifungal agents are few  and the range of fungal pathogens along with the population at risk continues to expand. However, although bacterial resistance has been the impetus behind the initiation and strengthening of antibiotic stewardship programmes in hospitals, fungal resistance is less of a problem being confined to certain contexts. Triazole resistance in Aspergillus fumigatus has been described in both azole-naive [7–9] and azole-exposed patients [7,8,10] mostly in patients with cavitatory disease , but also in patients with allergic aspergillosis and cancer patients with invasive aspergillosis . Alarmingly, high rates have been reported in the Netherlands, with 6–12.8% of clinical isolates harbouring resistance which has been associated with clinical failure of azole therapy [10–13]. Resistance appears to be geographically restricted to some settings within Europe but not others . Extensive use of azoles in agriculture is responsible , but the problem is likely under-recognized because of a paucity of field studies . Amongst Candida species, the issue of resistance largely applies to fluconazole and to a lesser extent the echinocandins . Longitudinal data from laboratory surveillance shows that fluconazole resistance amongst Candida albicans and Candida parasilopsis is uncommon, but Candida glabrata resistance may exceed 15% . Breakthrough candidaemia on caspofungin therapy has been documented in 2.4% of patients, being typically associated with prolonged therapy when source control of sepsis was not achieved .
PRINCIPLES OF STEWARDSHIP
Optimizing the use of currently available antifungal agents is principally driven by their high cost and attendant toxicities. We will focus on haematology–oncology patients because they are high users of antifungal agents  and have an established record of practice guidelines, but the principles discussed are applicable to other high users including intensive care unit (ICU) and solid-organ transplant (SOT) recipients. We will highlight some of the shared tenets with antibiotic stewardship and features peculiar to antifungal agents, while providing practical examples from our own experience in over 10 years of guideline development [18▪▪,19], implementation and computerized decision-support systems (CDSSs) [20,21] along with engagement with end-users and institutional stakeholders.
THE HEALTH AND ECONOMIC BURDEN OF INVASIVE FUNGAL DISEASES
Patients with acute myeloid leukaemia (AML) are at high risk for invasive fungal diseases (IFDs), particularly following remission-induction chemotherapy or treatment for refractory or relapsed disease , with historical rates of IFD complicating high-dose cytarabine-based chemotherapy reaching 36% . In recent clinical trials, IFD incidence rates in patients with AML/myelodysplastic syndrome (MDS) were higher than in allo-haematological stem cell transplant (HSCT) recipients [24–27], a finding consistent with earlier (1999–2003) Italian registry data showing IFD incidences of 16.9 and 8.2% amongst AML and allo-HSCT patients, respectively .
The low incidence of IFD (3.2%) recently reported by the TRANSNET consortium amongst HSCT recipients 12 months from transplantation is due to 60% of the denominator comprising autologous recipients who had the lowest incidence (1.2%) of IFDs overall . In fact, amongst HLA-mismatched related and unrelated allo-HSCT recipients, IFD incidence rates were 8.1 and 7.7%, respectively, with wide inter-institutional variation noted ranging from 3.1 to 20.6% amongst six sites with a high case-load . Marked institutional variation in IFD incidence is likely due to differences in case-mix, treatment practices, infection control and possibly geoclimatic factors . Mold infections predominated with invasive aspergillosis and zygomycoses accounting for 46 and 8%, respectively, followed by invasive candidiasis (28%) .
Although improvements in the short-term survival of invasive aspergillosis are encouraging, crude mortality remains considerable at 33–47% [22,31–33], and for patients surviving IFD the prospect of delays or modifications to curative chemotherapy may compromise long-term prognosis [23,34]. For HSCT recipients invasive candidiasis is not a benign disease, with a 12-month mortality similar to invasive aspergillosis of 67 and 75%, respectively .
Studies using large administrative datasets have reported that antifungal agents contribute 7–15% of total treatment costs of patients with IFDs [35–37], but this may be an underestimate. A recent single-centre study of haematology–oncology patients, using patient-level data and activity-based costing methods (a highly regarded costing tool ), showed that pharmacy costs accounted for 64% of the difference in mean hospital cost per patient [39▪▪]. Antifungal agents accounted for 27% of the overall difference (P < 0.001) with no significant differences seen in ward costs between infected and uninfected controls (27%, P = 0.091) [39▪▪]. The proportion of pharmacy (60%) to ward (31%) costs persisted at 12 weeks follow-up, suggesting that the finding was robust [39▪▪].
Pharmacoeconomic analyses are best informed by estimates of attributable cost. However, disentangling the effect of underlying illness in complex patients with cancer is challenging. Cost determination methods for IFDs have included gross costs [40,41], expert opinion  and clinical trial data [43,44]; but studies reporting attributable cost are few [35,39▪▪,45–47], and those using patient-level data are even rarer [39▪▪,47]. Attributable mean invasive aspergillosis-associated medical cost in patients with AML/MDS has been estimated to be €15 280 ; but given the skewed nature of health outcomes, reporting the mean may potentially overstate costs because of the effect of outlier patients. Median costs, in contrast, represent a conservative estimate which in one study resulted in an IFD attributable hospital cost of AU$30 957 (95% confidence interval, CI AU$2368 to AU$59 546; P = 0.034), approximating at purchasing power parity US$21 203 (95% CI US$1622 to US$40 784) and €15 788 (95% CI €1208 to €30 368) [39▪▪]. Costly antifungal treatment [C-AT, defined as liposomal amphotericin B, voriconazole, posaconazole, caspofungin expressed as defined daily doses (DDDs) per IFD hospitalization] was described as an alternative resource metric which may be more generalizable than cost alone, being independent of country and inflation. IFD was associated with an excess of 17 DDDs of C-AT (95% CI 15–19 DDDs; P < 0.001) per case patient [39▪▪].
It is the high mortality and morbidity of IFDs coupled with diagnostic uncertainty where culture positive rates in patients with confirmed invasive aspergillosis are only 30–50% , which drives the overuse of antifungal agents.
ESSENTIAL ELEMENTS OF AN ANTIFUNGAL STEWARDSHIP PROGRAMME
These are well described for AMS [4,18▪▪] but are applicable to AFS also.
Implementation of antifungal guidelines
Practice guidelines are the starting point on the AFS roadmap. Ideally, guidelines should be available at the point of care, whether embedded in CDSS or hospital intranet, and linked to access to expert prescribers such as infectious diseases physicians or clinical pharmacists. Integration into the decision-making process and work-flow of prescribers, who are typically busy junior staff, is likely to enhance their uptake. Clinical care pathways for the management of IFDs have recently been proposed as a means of integrating clinical guidelines with diagnostic protocols in a feasible way for multidisciplinary teams to deliver [49▪▪].
Guidelines adapted to the local context
The many national and international guidelines for the management of patients with IFDs [19,50–53,54▪▪] are designed to assist clinicians in providing appropriate evidence-based care. Although little is known about their impact on provider behaviour, it is clear that adaptation to local circumstances with input from senior clinicians is likely to increase acceptance rates . We accommodated deviations from national guidelines  with, for example, the use of intermittent liposomal amphotericin prophylaxis in patients intolerant of azole drugs , thereby increasing the acceptance of guidelines by our haematologists, their sense of ownership of the document and satisfaction with process.
Few studies have evaluated the translation of guidelines into practice. An evaluation of 136 cases of invasive aspergillosis from an Italian registry (2004–2007) found poor compliance with Infectious Diseases Society of America (IDSA) and European Conference on Infections in Leukaemia (ECIL) recommendations for first-line therapy, being 55 and 28%, respectively . Noncompliance with guidelines did not impact mortality but guideline adherence was associated with improved short-term clinical outcome. The authors concluded that guidelines are often inapplicable to daily practice, perhaps because patients with multiple comorbidities and organ dysfunction are excluded from the clinical trials which ultimately inform practice guidelines. A cautious interpretation of this study is warranted as this was a post hoc evaluation, used guidelines which were either outdated (IDSA 2000) or just published (ECIL 2007), examined appropriateness which is one of several components of prescribing quality and used a controversial endpoint, namely attributable rather than overall mortality assessed at 120 days rather than 6 weeks which may be regarded as a more accurate time point for IFD-related outcomes .
Given that empiric antifungal therapy (EAFT) accounts for the majority of inpatient antifungal prescription ranging from 62 to 72% [22,59] and recent recommendations advocating either voriconazole [54▪▪] or posaconazole prophylaxis [52,54▪▪] in high-risk haematology patients, these are the areas which at a minimum should be addressed by institutional guidelines.
Preprescription approval with postprescription review and feedback
Restrictive interventions such as formulary restriction and preprescription approval are more than three times more influential than persuasive interventions, such as education, on prescribing behaviour . Our web-based approval system allows doctors to obtain approval for standard (e.g. guideline concordant) and nonstandard or guideline discordant indications . All approvals are reviewed by the infectious diseases service within 24–48 h, but dispensing is not withheld pending infectious diseases review because it is impractical in a busy clinical service and risks unintended patient harm such as delaying the initiation of potentially life-saving therapy. Postprescription review and feedback is a core activity of AMS [4,18▪▪], whereby deficiencies in prescribing practice are identified by the AFS team and prescribers educated. In our setting, both methods are employed in a multifaceted approach using high visibility of AFS teams on regular rounds to build trust and encourage discussion with prescribers.
ANTIFUNGAL THERAPY: OPPORTUNITIES FOR IMPROVEMENT
Drug de-escalation and limiting empiric antifungal therapy are particular areas which require active guidance from AFS teams.
The challenges of de-escalation
Therapeutic streamlining is recommended by the IDSA in the management of candidiasis and invasive aspergillosis [51,52], but current guidelines under-appreciate the challenges of de-escalation in the empiric context . Even when susceptibility results are available to guide therapy, clinicians are often reluctant to de-escalate therapy when a seriously ill patient is improving on broad-spectrum treatment. A recent study of patients with candidaemia reported that less than 40% of echinocandin-treated patients with fluconazole-susceptible isolates were de-escalated to fluconazole and only 50% of patients with less severe disease or C. albicans underwent de-escalation . The solution, therefore, lies in building clinical confidence around de-escalation, but this is hampered by the suboptimal diagnosis of IFDs using current tests.
Restraining empiric antifungal use relies on improved diagnostics
A diagnostic-driven strategy or preemptive approach incorporating nonculture-based tests (NCBTs) such as galactomannan and Aspergillus PCR along with computed tomography (CT) aims to curtail unnecessary antifungal drug use and has best been studied in neutropenic patients. Most studies to date have shown a reduction in antifungal use [63–66], but the practice has attracted an experimental grading in the recent ECIL-3 guidelines [54▪▪] because noninferiority of the preemptive approach in a subgroup of leukaemic patients at very high risk of IFD (i.e. undergoing remission-induction chemotherapy) could not be demonstrated with certainty in one open-label randomized study, although no overall difference in mortality was seen between groups . Indeed, similar concerns were raised by Girmenia et al. who after comparing an intensive diagnostic approach to standard care, instituted posaconazole prophylaxis for patients with AML because of their high incidence of IFD. A lack of a consensus definition, target population, utility in patients on mold-active prophylaxis and cost-effectiveness need to be resolved before the preemptive approach is widely accepted.
Harnessing the excellent negative predicative value of NCBTs may be the most appropriate means of using them by excluding invasive aspergillosis with confidence [68▪▪]. A meta-analysis of mainly haematological patients concluded that the serum galactomannan assay for probable/proven invasive aspergillosis had a low postive predictive value of 31% (95% CI 26–53%) but a high negative predictive value (NPV) of 98% (95% CI 97–99%) . Similarly, studies have used the NPV of PCR as a screening tool in allo-HSCT and high-risk haematology patients to demonstrate no excess in mortality amongst patients in whom EAFT was withheld [64,70] and in one setting realized savings in antifungal drug expenditure .
Advances in molecular tests [71▪▪,72] will likely enhance AFS efforts. Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF) is emerging as a powerful tool for the rapid and reliable identification of Candida and Aspergillus species with the additional advantage of lower costs than ccnventional methods [73,74]. Similarly, rapid identification of azole resistance in culture-negative samples in patients with pulmonary aspergillosis using ultrasensitive real-time Aspergillus PCR has recently been reported , but the clinical relevance of this finding needs assessment.
Measuring the performance of an AFS programme: quality and quantity of prescribing
Demonstrating the continued benefit of an AFS programme to hospital administrators, drug committees and senior clinicians relies on the cyclical monitoring of process, outcome and structural measures (presented in Table 1) relevant to the prevention and management of IFDs. Initial goals should be modest and achievable in order to demonstrate success of the programme in the short term (i.e. ‘quick wins’). For example, targeting a few high-cost antifungal drugs which may have suboptimal use such as liposomal amphotericin, the echinocandins or intravenous voriconazole may be preferable to demonstrating a reduction in all antifungal drugs.
In addition to clinical audit, population-level surveys are a useful means of identifying areas requiring attention. Schelenz et al. reported several deficiencies in clinical and laboratory standards amongst UK hospitals including delayed initiation of antifungal therapy and central catheter-line removal in patients with candidaemia, low provision of on-site galactomannan testing and suboptimal morphological fungal description. In a recent survey, lung transplant clinicians flagged the need for structural measures, namely consensus guidelines on antifungal prophylaxis .
Process and outcome measures
Measurement of antifungal consumption and the use of this data to benchmark institutions is problematic because of differences in case-mix (e.g. transplant centres, ICU workload) or institutional practices (e.g. local guidelines, transplant practices) . Unit or ward-specific usage data should at a minimum include high users such as haematology–oncology and ICU patients [17,78,79]. Antifungal drug consumption in DDDs  has several limitations [81,82] and tends to overestimate the use for fluconazole, itraconazole and amphotericin B . Usage data is commonly reported as a mean [17,78], but a distribution (median, IQR) should be considered because it is more resistant to outlier patients who skew all resource metrics including length of stay (LOS), C-AT and hospital cost [39▪▪]. However, quantitative data, although relatively simple to obtain, is inherently limited by a lack of information on the appropriateness of prescribing [17,83].
The minimum standards of prescribing antimicrobials are well documented [4,18▪▪]. Cooke and Holmes  proposed a care bundle, denoting adherence to its individual elements, as a means of gauging the health of an institution's AMS programme, a proposition which has been recently tested . From an AFS perspective, maintaining high prescribing standards could be regarded as a surrogate for patient safety and improved clinical outcomes as it ensures that the most effective antifungal agent is being given and that drug-related adverse events are being minimized.
A clear association between appropriateness and timeliness of antimicrobial administration and clinical outcomes in sepsis/infectious diseases has been demonstrated [86,87] and IFDs are no exception. For patients with invasive candidiasis, the association between inadequate dosing or delayed initiation of antifungal therapy and increased LOS, healthcare costs, morbidity and mortality is well established [87–89]. Inadequate dosing of fluconazole is an independent predictor of mortality  and is common [90,91], being present in approximately half of critically ill patients and two-thirds of non-ICU patients in one single centre .
Improved diagnosis of IFD is central to guiding antifungal therapy but dependent on the timeliness and completeness of the diagnostic work-up. Characteristic radiological features of invasive aspergillosis such as the halo sign are associated with improved clinical response but, being transient, present in 88–96% of patients at day 0–1 but only 22–37% by day 7 , underscoring the importance of early CT scanning when IFD is suspected. Similarly, the diagnostic yield from bronchoscopy in HSCT recipients 100 days after transplant declines after clinical presentation (75% at day 1, 40% at day 5 and 14% at day 10) , indicating that referral should be prompt. Indeed, a single centre specializing in the management of patients with multiple myeloma endeavours to confirm the diagnosis of invasive aspergillosis using host, clinical and radiologic criteria within 24–48 h . Another modality, bronchoalveolar lavage fluid-based PCR diagnosis, in one study was associated with improved inpatient mortality compared with probable invasive aspergillosis (80 vs. 35.6%, P < 0.003) because the latter represents a more advanced stage of disease .
Clinical audit as a core AFS activity should evaluate the impact of formulary changes on IFD incidence. At our institution, consecutive use of fluconazole, itraconazole, voriconazole and posaconazole prophylaxis in 216 patients with AML/MDS undergoing high-dose cytarabine-based chemotherapy was associated with an incremental reduction in breakthrough IFD incidence of 25, 16, 14 and 3%, respectively . In contrast, intermittent liposomal amphotericin prophylaxis appears to be less effective with a breakthrough IFD incidence of 6.9%, prompting a review of our dosing regimen .
Relative to infections caused by multiresistant bacteria, IFDs have a lower institutional incidence but a high health and economic burden which is likely to increase over time as the population of at-risk individuals expands . Institutional variation in incidence rates , emerging but under-recognized antifungal resistance  and evolving treatment practices underscores the importance of centres knowing their local epidemiology, which can only be achieved with surveillance. The cornerstone of AFS is the implementation of institutional guidelines which should largely accord with international or national standards augmented by provider audit and feedback, the quality use of medicine indicators and performance measures [18▪▪,84]. An orchestrated effort requiring multidisciplinary team engaging and consensus building with end-users is vital for mission success. It is incumbent upon AFS programmes to demonstrate value to hospital administrators and although a reduction in healthcare costs is regarded as a secondary goal of AMS , it is a common justification for stewardship programmes  which should be exploited by AFS programmes also, given the high costs and high contribution of antifungal agents to the management and prevention of IFDs.
Authorship: study conception and design: M.A.S., K.T.T.; drafting of manuscript: M.R.A.; critical revision of manuscript: all authors.
A National Health and Medical Research Council postgraduate medical scholarship was given to M.R.A.
Conflicts of interest
M.R.A. and K.T.T. have no conflicts on interest. M.A.S. serves or has served on advisory boards for, has received investigator-initiated grants from and given lectures for Gilead Sciences, Pfizer, Merck, Schering Plough.
This study received no external funding.
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antifungal agents; antifungal stewardship; fungal infections
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