A systematic review of interventions and performance measures for antifungal stewardship programmes

A systematic review of interventions and performance measures for antifungal stewardship programmes Abstract Objectives Antifungal resistance is a significant and emerging threat. Stewardship programmes (SPs) have been proposed as an opportunity to optimize antifungal use. While examples of antifungal SP implementation have been recently described, there is yet to be an overview of interventions and their impacts on performance measures. Methods We systematically reviewed published articles using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses check-list 2009. MEDLINE was searched using the term ‘antifungal stewardship’ on 15 February 2017. Eligible studies were those that described an antifungal SP and included an intervention and an evaluation of performance measures. Results A total of 97 studies were identified and 14 were included. Only five studies reported an antifungal stewardship team composed of all the recommended members. The main intervention was the formulation of recommendations to change treatment (12 of 14). The main performance measure collected was antifungal consumption (10 of 14), followed by antifungal expenditure (7 of 14), adherence to therapeutic advice (4 of 14) and impact on mortality (4 of 14). Antifungal consumption was reduced by 11.8% to 71% and antifungal expenditure by as much as 50%. Adherence to therapeutic advice ranged from 40% to 88%, whereas antifungal SPs had no impact on mortality. Conclusions All antifungal SPs had an impact, in particular on antifungal consumption and antifungal expenditure. Active intervention including a review of prescriptions seems to have more impact than implementation of treatment guidelines only. According to available published studies, antifungal consumption appears to be the most achievable performance measure to evaluate the impact of an antifungal SP. Introduction Antimicrobial resistance is a major public health concern and is identified by the WHO as one of the three greatest threats to human health.1 The development of resistance is related to excessive use of antimicrobial drugs. In this context, antibiotic stewardship programmes (SPs) have been proposed as an opportunity to contain antimicrobial resistance.2,3 They are supported by guidelines published by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America.4,5 The benefits of antibiotic SP are well-known and include improved patient outcomes, reduction of adverse events including Clostridium difficile infections, reduction in antibiotic resistance and optimization of resource consumption.4,5 Resistance concerns are not limited to antibacterials as antifungal resistance is also a significant and emerging threat, mainly to azoles for Candida and Aspergillus: resistance rates were reported between 11.9% and 14% for Candida glabrata and over 2.3% for Aspergillus fumigatus, with higher rates in some regions reflecting disparities in microbiological procedures to detect resistance.6 As demonstrated for antibiotics, inappropriate antifungal use contributes to an increase in resistance, mortality, morbidity and costs.7 While antibiotic SPs are widely implemented,8 few implementations of antifungal SPs have been reported in the literature. Antifungal SP is defined as an optimal use of antifungals through careful selection of agents based on patient profile, target organism, toxicity, cost, as well as the likelihood of emergence and spread of antifungal resistance.9 Antifungal SP initiatives aim to improve outcomes, avoid adverse drug-related effects, reduce emergence of resistance, more rapidly diagnose the fungal agent and control costs.7 While antifungal SP implementation has been recently described in reviews of the literature,7,9–15 there is yet to be an overview of interventions and their impact on performance measures. The objective of this study was therefore to analyse systematically the antifungal SP studies to describe interventions and their impact on performance measures. Methods Eligibility criteria Studies that described an antifungal SP and included an intervention and a performance measure were eligible; reviews, non-interventional studies, as well as those not written in English, were excluded. Search and information sources MEDLINE was searched using the term ‘antifungal stewardship’ (Search details: ‘antifungal agents’[Pharmacological Action] OR ‘antifungal agents’[MeSH Terms] OR (‘antifungal’[All Fields] AND ‘agents’[All Fields]) OR ‘antifungal agents’[All Fields] OR ‘antifungal’[All Fields]) AND stewardship [All Fields]). No filter or date limitation was used; the last search was performed on 15 February 2017. Study selection After screening the 97 records for duplicates, abstracts were uploaded in MEDLINE to assess eligibility of articles. If the abstract was not informative to assess eligibility, full texts were retrieved from the university library. To increase the completeness of the search, a snowballing approach was used: references of eligible articles and pertinent reviews were scanned.16 To resolve disagreement for inclusion, full-text articles were read in full independently by two investigators (A. L. B. and G. L.) leading to a consensus after discussion. Data extraction The full texts of the included articles were retrieved from the university library. Information about context, objectives, number of patients or reviewed prescriptions, interventions and performance measures [antifungal use, adherence to therapeutic advice, quality of care, mortality, incidence of invasive fungal infection (IFI)] was extracted after each included full-text article was read in full. To ensure reproducibility and completeness of data extraction, an Excel spreadsheet (Microsoft Corp., Redmond, WA, USA) compiling all variables to be extracted was used. Data extraction was double-checked by A. L. B. and G. L. Disagreements over data extraction were resolved by discussion. Data were centrally checked by an independent operator for completeness, plausibility and integrity before synthesis. Synthesis of results and summary measures The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) check-list 2009 was used as a methodological support of the systematic review.17 A narrative synthesis approach was used to summarize data extracted from full-text articles. Results A total of 97 records were identified; one record18 was identified using a snowballing approach. Among the 97 records, 64 did not describe an antifungal SP and were excluded. Among the 33 full texts assessed, 16 were antifungal SP reviews, two were non-interventional studies and one was not written in English; these articles were excluded. Thus, 14 studies were eligible for systematic review (Figure 1). Figure 1. View largeDownload slide PRISMA flow diagram mapping out the number of records identified, included and excluded, and the reasons for exclusions. Figure 1. View largeDownload slide PRISMA flow diagram mapping out the number of records identified, included and excluded, and the reasons for exclusions. Half of the studies were published in 2014 or later. The first study describing an antifungal SP with an intervention was published in 2009; its objective was to evaluate the impact of implementing practice guidelines for antifungal therapy in a surgical intensive care unit on the use and cost of antifungals.18 Three (of 14) studies19–21 were specifically dedicated to candidaemia, and 1 (of 14)22 also included data on antibiotic SP. Nine of 14 studies were conducted in tertiary care hospitals, and five in university hospitals (Table 1). To collect information about the initiation of antifungal treatment, most studies (10 of 12) used pharmacy data, one study used microbiology data23 and one study was based on regular visits to a haematology unit24 (Table 1). Table 1 . Description of studies included in the systematic review Reference  Context/team  Objectives/method or request handling  Antifungals  Study period  Number of patients or prescriptions  Swoboda et al. (2009)18  University hospital, Heidelberg, Germany  To outline the impact of a standardized practice for ATF treatments  AmB, CAS, FLC, ITC, LAmB, POS, VRC  2005–07. 18 months before and 18 months after implementation of guidelines  Unreported  Team = not applicable (no review of prescriptions)  Method = practice guidelines imposed by the consultant responsible for ATF strategies and the head of intensive care unit  Apisarnthanarak et al. (2010)20  Thammasat University hospital, tertiary hospital, 350 beds, Pratumthani, Thailand  To evaluate the impact of education and ATF SP on prescribing practices, ATF consumption, Candida species infection and cost  CAS, FLC, ITC, LAmB, VRC  2006–08. 1.5 years before and 1.5 years after the implementation of ATF SP  1106 patients  Team = 3 members  Request handling = ATF prescription  López-Medrano et al. (2013)26  University-affiliated Hospital 12 de Octubre, Madrid, Spain  To review prescriptions and make non-compulsory recommendations  CAS, LAmB, VRC  2008–09. 24 months  662 prescriptions  Team = 3 members  Request handling = all ATF prescriptions checked every working day from the computerized system of the pharmacy  Standiford et al. (2012)22  Tertiary care academic medical centre, Baltimore, USA  To evaluate the cost before, during and after the programme  All antimicrobials including ABLC, AmB, CAS, FLC, LAmB, MIC, VRC  2001–10. 2001 before implementation/2002–08 during implementation/2009–10 after implementation  Unreported  Team = ID specialist and pharmacist  Request handling = antimicrobial orders  Antworth et al. (2013)19  Academic Hospital, 930 beds, Michigan, USA  To analyse the impact of a care bundle by antimicrobial stewardship team on the management of candidaemia  Candins, LAmB, POS, VRC  2010–11. 7 months non-interventional/7 months interventional  78 patients  Team = ID specialist and pharmacist  Request handling = real-time surveillance of clinical decision support software  Guarascio et al. (2013)31  University Hospital, 450 beds, TN, USA  To evaluate utility of ATF bundle in limiting excessive use of echinocandins in intensive care unit  CAS  6 months  108 patients  Team = pharmacist  Request handling = prescription of caspofungin  Mondain et al. (2013)28  Teaching tertiary care hospital, 1800 beds, Nice, France  To describe and assess ATF SP impact on ATF prescriptions and their costs  Candins, LAmB, POS, VRC  2005–10. 5 years  636 prescriptions  Team = ID specialist and pharmacist  Request handling = ATF prescription  Alfandari et al. (2014)24  University Hospital, Lille, France  To implement ATF SP  CAS, LAmB, VRC  2009–10. 24 months  192 patients  Team = ID specialist  Request handling = visit of haematology unit twice a week  Reed et al. (2014)23  Teaching Hospital, 1229 beds, OH, USA  To evaluate impact of ATF SP pharmacist’s intervention on time to effective ATF, in-hospital mortality, infections, length of stay and costs  ABLC, AmB, CAS, FLC  2008 and 2010. 1 year 2008 compared with 1 year 2010  173 patients  Team = 3 members  Request handling = microbiology laboratory notification of a yeast to the pharmacist and electronic list of patients with Candida positive blood culture  Ramos et al. (2015)27  Tertiary Hospital Puerta de Hierro, Madrid, Spain  To evaluate efficiency of ASP  Candins, LAmB, VRC  Oct 2012–May 2013. 8 months  280 prescriptions  Team = 3 members  Request handling = electronic medical record including prescriptions and progress notes  Valerio et al. (2015)25  Tertiary Hospital, Gregorio Maranon, Madrid, Spain  To describe a bedside non-restrictive ATF SP and evaluate its economic impact  Candins, LAmB, POS, VRC  Oct 2010–Sept 2012. 12 months non-interventional/12 months interventional  453 patients  Team = 3 members  Request handling = non-compulsory computerized physician order, which alerts pharmacist of a new ATF prescription  Micallef et al. (2015)29  Tertiary referral Hospital, Cambridge, England  To conduct an observational prospective study by an ASP team targeting the use of ATFs  CAS, LAmB, MIC, VRC  July 2013–June 2014. 12 months  173 patients  Team = pharmacist and microbiologist  Request handling = interrogation of the pharmacy system on systemic ATFs  Cook and Gooch (2015)21  Tertiary care teaching Hospital, 904 beds, Greenville, USA  To evaluate the impact of an antimicrobial stewardship on antimicrobial use including ATF  ABLC, MIC, POS, VRC  2001–13. 13 years  Unreported  Team = ID specialist and pharmacist  Request handling = computer-generated report of all patients receiving controlled and restricted drugs  Marzolini et al. (2016)30  University College London Cancer Institute, London, UK  To evaluate compliance and safety of a modified guideline incorporating direction for the cessation of ATF to decrease expenditure of POS  POS  June 2012–July 2014. 24 months  42 patients  Team = not applicable (no review of prescriptions)  Method = retrospective study of conversion to POS  Reference  Context/team  Objectives/method or request handling  Antifungals  Study period  Number of patients or prescriptions  Swoboda et al. (2009)18  University hospital, Heidelberg, Germany  To outline the impact of a standardized practice for ATF treatments  AmB, CAS, FLC, ITC, LAmB, POS, VRC  2005–07. 18 months before and 18 months after implementation of guidelines  Unreported  Team = not applicable (no review of prescriptions)  Method = practice guidelines imposed by the consultant responsible for ATF strategies and the head of intensive care unit  Apisarnthanarak et al. (2010)20  Thammasat University hospital, tertiary hospital, 350 beds, Pratumthani, Thailand  To evaluate the impact of education and ATF SP on prescribing practices, ATF consumption, Candida species infection and cost  CAS, FLC, ITC, LAmB, VRC  2006–08. 1.5 years before and 1.5 years after the implementation of ATF SP  1106 patients  Team = 3 members  Request handling = ATF prescription  López-Medrano et al. (2013)26  University-affiliated Hospital 12 de Octubre, Madrid, Spain  To review prescriptions and make non-compulsory recommendations  CAS, LAmB, VRC  2008–09. 24 months  662 prescriptions  Team = 3 members  Request handling = all ATF prescriptions checked every working day from the computerized system of the pharmacy  Standiford et al. (2012)22  Tertiary care academic medical centre, Baltimore, USA  To evaluate the cost before, during and after the programme  All antimicrobials including ABLC, AmB, CAS, FLC, LAmB, MIC, VRC  2001–10. 2001 before implementation/2002–08 during implementation/2009–10 after implementation  Unreported  Team = ID specialist and pharmacist  Request handling = antimicrobial orders  Antworth et al. (2013)19  Academic Hospital, 930 beds, Michigan, USA  To analyse the impact of a care bundle by antimicrobial stewardship team on the management of candidaemia  Candins, LAmB, POS, VRC  2010–11. 7 months non-interventional/7 months interventional  78 patients  Team = ID specialist and pharmacist  Request handling = real-time surveillance of clinical decision support software  Guarascio et al. (2013)31  University Hospital, 450 beds, TN, USA  To evaluate utility of ATF bundle in limiting excessive use of echinocandins in intensive care unit  CAS  6 months  108 patients  Team = pharmacist  Request handling = prescription of caspofungin  Mondain et al. (2013)28  Teaching tertiary care hospital, 1800 beds, Nice, France  To describe and assess ATF SP impact on ATF prescriptions and their costs  Candins, LAmB, POS, VRC  2005–10. 5 years  636 prescriptions  Team = ID specialist and pharmacist  Request handling = ATF prescription  Alfandari et al. (2014)24  University Hospital, Lille, France  To implement ATF SP  CAS, LAmB, VRC  2009–10. 24 months  192 patients  Team = ID specialist  Request handling = visit of haematology unit twice a week  Reed et al. (2014)23  Teaching Hospital, 1229 beds, OH, USA  To evaluate impact of ATF SP pharmacist’s intervention on time to effective ATF, in-hospital mortality, infections, length of stay and costs  ABLC, AmB, CAS, FLC  2008 and 2010. 1 year 2008 compared with 1 year 2010  173 patients  Team = 3 members  Request handling = microbiology laboratory notification of a yeast to the pharmacist and electronic list of patients with Candida positive blood culture  Ramos et al. (2015)27  Tertiary Hospital Puerta de Hierro, Madrid, Spain  To evaluate efficiency of ASP  Candins, LAmB, VRC  Oct 2012–May 2013. 8 months  280 prescriptions  Team = 3 members  Request handling = electronic medical record including prescriptions and progress notes  Valerio et al. (2015)25  Tertiary Hospital, Gregorio Maranon, Madrid, Spain  To describe a bedside non-restrictive ATF SP and evaluate its economic impact  Candins, LAmB, POS, VRC  Oct 2010–Sept 2012. 12 months non-interventional/12 months interventional  453 patients  Team = 3 members  Request handling = non-compulsory computerized physician order, which alerts pharmacist of a new ATF prescription  Micallef et al. (2015)29  Tertiary referral Hospital, Cambridge, England  To conduct an observational prospective study by an ASP team targeting the use of ATFs  CAS, LAmB, MIC, VRC  July 2013–June 2014. 12 months  173 patients  Team = pharmacist and microbiologist  Request handling = interrogation of the pharmacy system on systemic ATFs  Cook and Gooch (2015)21  Tertiary care teaching Hospital, 904 beds, Greenville, USA  To evaluate the impact of an antimicrobial stewardship on antimicrobial use including ATF  ABLC, MIC, POS, VRC  2001–13. 13 years  Unreported  Team = ID specialist and pharmacist  Request handling = computer-generated report of all patients receiving controlled and restricted drugs  Marzolini et al. (2016)30  University College London Cancer Institute, London, UK  To evaluate compliance and safety of a modified guideline incorporating direction for the cessation of ATF to decrease expenditure of POS  POS  June 2012–July 2014. 24 months  42 patients  Team = not applicable (no review of prescriptions)  Method = retrospective study of conversion to POS  ABLC, amphotericin B lipid complex; AmB, amphotericin B desoxycholate; ASP, antifungal stewardship; ATF, antifungal; CAS, caspofungin; FLC, fluconazole; ITC, itraconazole; LAmB, liposomal amphotericin B; MIC, micafungin; POS, posaconazole; VRC, voriconazole. The objective of the studies was to evaluate the impact on antifungal use of a review of prescription (12 of 14) or implementation of practice guidelines (2 of 14). The study period ranged from 6 months to 13 years (Table 1); the median study duration was 1 year. Five studies incorporated a non-interventional period considered as a control period that doubles the time of the study (Table 1).18–20,23,25 Among the 12 studies that included a review of prescriptions, only five reported an antifungal stewardship team composed of all the recommended members [i.e. an infectious disease (ID) specialist, a clinical pharmacist and a clinical microbiologist];20,23,25–27 four lacked a clinical microbiologist,19,21,22,28 one lacked an ID specialist,29 one lacked an ID specialist and a clinical microbiologist,24 and one lacked a clinical microbiologist and a clinical pharmacist.24 All studies (n = 12) included in their review of prescriptions echinocandins, liposomal or lipid complex amphotericin B, voriconazole and posaconazole. Two studies also included fluconazole18,20 and two studies included fluconazole and itraconazole18,20 (Table 1). A mean of 258 patients (range 42–1106) were included in the studies (n = 9) and a mean of 526 (range 280–662) prescriptions were reviewed (n = 3); the number of patients and prescriptions were not reported for two studies.18,22 Among studies in which all core members were represented in the antifungal stewardship team (n = 5), a mean of 577 patients (range 453–1106) were reviewed, and in studies in which the team lacked at least one member (n = 7), a mean of 137 patients (range 78–192) were reviewed. Among the 14 articles included in the present review, the most frequent intervention was the formulation of recommendations to change treatment (12 of 14; Table 2). In the majority of studies (10 of 14), the recommendations were formulated directly to the clinician in charge of the patient, and in the remaining studies (2 of 14), the recommendations were included in an electronic medical record.21,27 In two (of 14) studies, the only intervention was the implementation of practice guidelines.18,30 A minimum of three performance measures were collected in half of the studies including a review of prescription (6 of 12). Among the studies with a complete stewardship team (n = 5), more than three performance measures were collected, and in studies with an incomplete stewardship team, one (1 of 7) or two (5 of 7) measures were collected (Table 2). Table 2. Description of interventions and performance measures used in the studies included in the review References  Interventions  Performance measures   antifungal use  cost  adherence to therapeutic advice  quality of care  mortality  incidence of IFI  other  Swoboda et al. (2009)18  Implementation of practice guidelines  ↓ >50%  ↓ 50%            Apisarnthanarak et al. (2010)20  Education, ATF hepatic and renal adjustment tool, ATF prescription form, bedside case management  ↓ 59%, ↓ 51.6% DDD (FLC)  $31615          ↓ 47% inappropriate ATF, C. glabrata and krusei incidence, ↑ C. albicans incidence  López-Medrano et al. (2013)26  Recommendation to change treatment personally discussed with the clinician  ↓ DDD (VRC 31.4%, CAS 20.2%)  ↓ 11.8%    No reduction, no increase in persistent candidaemia  No increase  No increase  No increase in fluconazole-resistant Candida  Standiford et al. (2012)22  Active computer real-time review, active intervention when necessary    ↓ 45.8%            Antworth et al. (2013)19  Education on candidaemia management, recommendations on appropriate ATF and duration, removal of catheter, request for repeat blood culture and ophthalmological examination, encourage ID consultation if necessary  Fewer excess days of therapy (5 vs 83 days)      Rate of persistent or recurrent candidaemia similar, LOS similar, time until clearance of candidaemia similar      ↑ 21.9% ophthalmological examination, ↑ 13.5% appropriate ATF, ↑ 29.9% appropriate duration  Guarascio et al. (2013)31  Assist clinicians with ongoing awareness and reassessment of treatment plans at critical points during therapy  ↓ days of CAS (2 days)  $1013 per patient            Mondain et al. (2013)28  Post-prescription review during a weekly meeting, antimicrobial order form set-up, emergency tomodensitometry, on-site TDM for VRC and POS, diagnostic tool availability      88%  Improvement        Alfandari et al. (2014)24  Discussion of prescriptions, telephone counselling, training meetings, draft guidelines  ↓ 40%          Stable    Reed et al. (2014)23  Candidaemia guideline development, recommendations by the pharmacist for initiation of ATF, ID and ophthalmology consult, CVC removal, de-escalation, IV to oral conversion    Similar hospital cost    Similar LOS  Similar    ↓ 12.2 h time to effective therapy  Ramos et al. (2015)27  Programmed review of restricted ATFs, recommendation in the electronic medical record  ↓ 42%    40%    Similar      Valerio et al. (2015)25  Therapeutic recommendations by an ID specialist  ↓ DDD 17%  ↓ 21.7%      Similar  No reduction    Micallef et al. (2015)29  Clinical advice    ↓ 9.7%  50%          Cook and Gooch (2015)21  Review of prescriptions, prior approval for restricted antimicrobials, recommendations by electronic support  ↓ 71%    Increase of 9.2%          Marzolini et al. (2016)30  Adoption of a modified guideline              98% compliance to guideline  References  Interventions  Performance measures   antifungal use  cost  adherence to therapeutic advice  quality of care  mortality  incidence of IFI  other  Swoboda et al. (2009)18  Implementation of practice guidelines  ↓ >50%  ↓ 50%            Apisarnthanarak et al. (2010)20  Education, ATF hepatic and renal adjustment tool, ATF prescription form, bedside case management  ↓ 59%, ↓ 51.6% DDD (FLC)  $31615          ↓ 47% inappropriate ATF, C. glabrata and krusei incidence, ↑ C. albicans incidence  López-Medrano et al. (2013)26  Recommendation to change treatment personally discussed with the clinician  ↓ DDD (VRC 31.4%, CAS 20.2%)  ↓ 11.8%    No reduction, no increase in persistent candidaemia  No increase  No increase  No increase in fluconazole-resistant Candida  Standiford et al. (2012)22  Active computer real-time review, active intervention when necessary    ↓ 45.8%            Antworth et al. (2013)19  Education on candidaemia management, recommendations on appropriate ATF and duration, removal of catheter, request for repeat blood culture and ophthalmological examination, encourage ID consultation if necessary  Fewer excess days of therapy (5 vs 83 days)      Rate of persistent or recurrent candidaemia similar, LOS similar, time until clearance of candidaemia similar      ↑ 21.9% ophthalmological examination, ↑ 13.5% appropriate ATF, ↑ 29.9% appropriate duration  Guarascio et al. (2013)31  Assist clinicians with ongoing awareness and reassessment of treatment plans at critical points during therapy  ↓ days of CAS (2 days)  $1013 per patient            Mondain et al. (2013)28  Post-prescription review during a weekly meeting, antimicrobial order form set-up, emergency tomodensitometry, on-site TDM for VRC and POS, diagnostic tool availability      88%  Improvement        Alfandari et al. (2014)24  Discussion of prescriptions, telephone counselling, training meetings, draft guidelines  ↓ 40%          Stable    Reed et al. (2014)23  Candidaemia guideline development, recommendations by the pharmacist for initiation of ATF, ID and ophthalmology consult, CVC removal, de-escalation, IV to oral conversion    Similar hospital cost    Similar LOS  Similar    ↓ 12.2 h time to effective therapy  Ramos et al. (2015)27  Programmed review of restricted ATFs, recommendation in the electronic medical record  ↓ 42%    40%    Similar      Valerio et al. (2015)25  Therapeutic recommendations by an ID specialist  ↓ DDD 17%  ↓ 21.7%      Similar  No reduction    Micallef et al. (2015)29  Clinical advice    ↓ 9.7%  50%          Cook and Gooch (2015)21  Review of prescriptions, prior approval for restricted antimicrobials, recommendations by electronic support  ↓ 71%    Increase of 9.2%          Marzolini et al. (2016)30  Adoption of a modified guideline              98% compliance to guideline  ATF, antifungal; CAS, caspofungin; CVC, central venous catheter; FLC, fluconazole; IV, intravenous; LOS, length of stay; POS, posaconazole; VRC, voriconazole; TDM, therapeutic drug monitoring. The most frequent performance measure collected was antifungal consumption (10 of 14): reduction in consumption ranged from 11.8% to 71%, and reduction in DDD ranged from 17% to 52% (3 of 14). A reduction of 2 days of therapy was reported from one study.31 A reduction of antifungal cost was found in half of the studies (7 of 14), and cost containment was reported in one study.23 A decrease of 50% in antifungal use and >50% in antifungal cost was reported in one of the two studies based on implementation of treatment guidelines only (Table 2).18 Adherence to therapeutic advice was evaluated in four of the 12 studies that included a review of prescription and ranged from 40% to 88%. Among these, one study used an electronic medical record and found 40% adherence.27 The impact of antifungal SP in terms of mortality was evaluated in 4 of 14 studies, and in terms of IFI incidence in 3 of 14 studies. From these studies, no impact on mortality or on IFI incidence was observed. Conversely, one of the four studies that investigated quality of care found an improvement in this measure. Other performance measures were reported, e.g. the proportion of appropriate prescriptions20 and time to effective therapy,23 which were improved by antifungal SPs. For studies focusing on candidaemia,19–21 incidences of Candida krusei, C. glabrata, and Candida albicans were evaluated, as was the time to clearance of candidaemia and rate of ophthalmological examinations. Antifungal SPs had a positive impact on the rate of resistant Candida20 and ophthalmological examinations19 (Table 2). Discussion Antifungal stewardship is a recent matter of debate, which is illustrated by the publication date of the included studies, the majority of which were published from 2014. It was found from this review that antifungal SPs were implemented in tertiary care hospitals or university hospitals, which can be explained by the frequent use of these drugs in critically ill patients admitted to such healthcare structures, as well as the availability of human resources and facilities required to implement antifungal SP.8 The role of the multidisciplinary team to ensure optimal management of IFI is unquestionable.32 It should include ID specialists, a clinical pharmacist and a clinical microbiologist.7 However, among the 12 articles including a review of prescription, only five articles reported a complete antifungal stewardship team. An information system specialist, infection control professional and hospital epidemiologist are also included in the antibiotic SP team according to IDSA guidelines.5 It is of note that none of the included studies had a stewardship team that included such healthcare professionals and the recommendations for antifungal SP do not stipulate the inclusion of these. Interestingly, among the studies included herein, the number of prescriptions reviewed and performance measures collected were greater if the antifungal stewardship team was complete, which suggests more extensive investigations are performed when the required human resources are allocated to the SP. This is in accordance with a review describing Australasian resources and activities for antimicrobial SP from which it appears that a lack of personnel involved in SP was a barrier to successful antimicrobial SP.33 Furthermore, it has been suggested that the absence of a pharmacist is associated with an increased rate of inappropriate antimicrobial use and an increased duration of treatment.34 However, it is not possible to comment further on this aspect from the studies included herein; only one study did not include a pharmacist, and furthermore did not report on these parameters.24 The most frequent intervention was the formulation of recommendations to change treatment. According to Muñoz et al.,12 formulation of therapeutic advice is part of the persuasive interventions that require more time and effort, but which have long-term acceptance. In one of the two studies only based on implementation of guidelines,35 authors obtained an impact on antifungal consumption and cost, but it is not indicated if the action was sustainable or not. An interesting future development in antifungal SP may be the use of rapid diagnostic tests, including Candida molecular diagnostic techniques, which have been proposed by Goff et al.35 and Denning et al.36 to optimize antimicrobial selection, control antimicrobial resistance and improve clinical outcome; to our knowledge, the impact of this intervention through an antifungal SP has yet to be evaluated. Muñoz et al.12 also noted that indicators are mandatory for antifungal SP. Two types of indicators are required: process measures, and outcome measures.10 This has been further detailed by Ananda-Rajah et al.11 who published a detailed list of performance measures for antifungal SP: process measures include antifungal drug consumption, minimum standards of prescribing, therapeutic streamlining, timeliness and completeness of diagnostic investigations when IFI is suspected, and concordance of prescribing with institutional guidelines; outcome measures include IFI incidence in targeted groups and antifungal drug expenditure. Moreover, Ananda-Rajah et al.11 created a specific performance measure for antifungal SP named ‘structural measures’ that include an antifungal drug policy and locally adapted practice guidelines. Conversely, bundle of care indicators in patients with candidaemia were specifically developed by Miyazaki and Kohno13 and extensively reviewed by Pfaller and Castanheira14 and Ruhnke15 Interestingly, all types of performance measures were collected in the 14 studies included in the present review. It has to be noted that only a few studies evaluated the impact of antifungal SP on IFI incidence and mortality, as a good indication of quality of care: this is in accordance with IDSA guidelines that consider measurement of antibiotic SP impact on outcome more challenging than measuring antibiotic use or guideline compliance.5 The most frequent process measure was antifungal consumption using DDD. According to IDSA guidelines, days of therapy are preferred because they are not impacted by dose adjustments and can be used in paediatrics when weight-based dosing is required. However, DDDs remain an alternative if patient-level antimicrobial use data cannot be obtained.5 The second most frequent process measure collected was the agreement of prescribing with treatment guidelines. Near perfect agreement was obtained in an antifungal SP that was only based on implementation of modified guidelines.30 The level of adherence to therapeutic advice was also evaluated in four studies and it is of note that the lowest adherence was obtained using an electronic medical record to formulate therapeutic advice;27 direct interactions with the clinicians in charge of the patient seem more efficient to obtain better compliance.28 The most frequent outcome measure (reported in half of included studies) was antifungal expenditure; although cost is considered to be a secondary goal for antimicrobial stewardship, cost saving is one way to justify continued administrative support for antimicrobial SP activities.5 All studies included herein focused on high-cost antifungals and only a few also included fluconazole and itraconazole.18,20,22,23 It could, however, be of interest to study fluconazole resistance, as the potential of fluconazole to induce resistance in Candida is high. However, it has to be noted that resistance as an indicator of SP is considered by IDSA guidelines to be a very complex metric because resistance development and spread is multifactorial.5 In antifungal SP, only two studies evaluated Candida resistance;20,26 one reported a lower level of resistant Candida after an antifungal SP implementation.20 Length of hospitalization, days of hospitalization avoided, as well as parenteral therapy and days of central venous access avoided, are preferred metrics for antibiotic SP because it is a consequence of therapeutic streamlining.5 From the 14 studies, only two related to candidaemia evaluated the length of hospitalization that remained unchanged despite antifungal SP. Surprisingly, among the outcome measures reported in the included studies, occurrence of adverse events was not used. The main limitation of this systematic review is the low number of research papers on the topic. Incomplete retrieval is possible for papers outside MEDLINE. Conclusions All antifungal SPs included in this systematic review had an impact on antifungal prescription, in particular on antifungal consumption and antifungal expenditure. The multidisciplinary team, as well as face-to-face discussion about antifungal prescription, appear to be cornerstones of antifungal SP. A future direction could be the development of guidelines for antifungal SP implementation, as is currently the case for antibiotics. Acknowledgements We thank Philip Robinson (DRCI, Hospices Civils de Lyon) for his helpful comments. Funding This study was carried out as part of our routine work. Transparency declarations Nothing to declare. Author contributions A. L. B. conceived the project, collated the search results, reviewed data in PRISMA format, drafted, compiled and approved the final report. L. A., E. J., V. P. and T. R. reviewed data, edited the manuscript and approved the final report.  F. A., J. L. F. and C. G. reviewed data and approved the final report. C. C. conceived the project and approved the final report. G. L. conceived the project, reviewed data and approved the final report. Data sharing The full dataset is available from the corresponding author. References 1 McLoughlin H. Conference report from International Congress on Infectious Diseases 2014: part 2. Future Microbiol  2014; 9: 1299– 301. Google Scholar CrossRef Search ADS PubMed  2 Verweij P, Lyon S. Optimizing antifungal strategies to improve patient survival. Future Microbiol  2016; doi:10.2217/fmb-2016-0153. 3 Laxminarayan R, Duse A, Wattal C et al.   Antibiotic resistance-the need for global solutions. Lancet Infect Dis  2013; 13: 1057– 98. Google Scholar CrossRef Search ADS PubMed  4 Barlam TF, Cosgrove SE, Abbo LM et al.   Implementing an Antibiotic Stewardship Program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis  2016; 62: e51– 77. Google Scholar CrossRef Search ADS PubMed  5 Dellit TH, Owens RC, McGowan JE et al.   Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis  2007; 44: 159– 77. Google Scholar CrossRef Search ADS PubMed  6 Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A. The global problem of antifungal resistance: prevalence, mechanisms, and management. Lancet Infect Dis  2017; doi:10.1016/S1473-3099(17)30316-X. 7 Muñoz P, Valerio M, Vena A et al.   Antifungal stewardship in daily practice and health economic implications. Mycoses  2015; 58 Suppl 2: 14– 25. Google Scholar CrossRef Search ADS PubMed  8 Goff DA, Kullar R, Goldstein EJC et al.   A global call from five countries to collaborate in antibiotic stewardship: united we succeed, divided we might fail. Lancet Infect Dis  2017; 17: e56– 63. Google Scholar CrossRef Search ADS PubMed  9 Wattal C, Chakrabarti A, Oberoi JK et al.   Issues in antifungal stewardship: an opportunity that should not be lost. J Antimicrob Chemother  2017; 72: 969– 74. Google Scholar PubMed  10 Hamdy RF, Zaoutis TE, Seo SK. Antifungal stewardship considerations for adults and pediatrics. Virulence  2016; 0: 1– 15. 11 Ananda-Rajah MR, Slavin MA, Thursky KT. The case for antifungal stewardship. Curr Opin Infect Dis  2012; 25: 107– 15. Google Scholar CrossRef Search ADS PubMed  12 Muñoz P, Bouza E; COMIC (Collaboration Group on Mycosis) study group. The current treatment landscape: the need for antifungal stewardship programmes. J Antimicrob Chemother  2016; 71: ii5– 12. Google Scholar CrossRef Search ADS PubMed  13 Miyazaki T, Kohno S. Current recommendations and importance of antifungal stewardship for the management of invasive candidiasis. Expert Rev Anti Infect Ther  2015; 13: 1171– 83. Google Scholar CrossRef Search ADS PubMed  14 Pfaller MA, Castanheira M. Nosocomial candidiasis: antifungal stewardship and the importance of rapid diagnosis. Med Mycol  2016; 54: 1– 22. Google Scholar PubMed  15 Ruhnke M. Antifungal stewardship in invasive Candida infections. Clin Microbiol Infect  2014; 20 Suppl 6: 11– 8. Google Scholar CrossRef Search ADS PubMed  16 Sayers A. Tips and tricks in performing a systematic review. Br J Gen Pract  2007; 57: 759. Google Scholar CrossRef Search ADS   17 PRISMA. http://prisma-statement.org/PRISMAStatement/Checklist.aspx. 18 Swoboda S, Lichtenstern C, Ober MC et al.   Implementation of practice guidelines for antifungal therapy in a surgical intensive care unit and its impact on use and costs. Chemotherapy  2009; 55: 418– 24. Google Scholar CrossRef Search ADS PubMed  19 Antworth A, Collins CD, Kunapuli A et al.   Impact of an antimicrobial stewardship program comprehensive care bundle on management of candidemia. Pharmacotherapy  2013; 33: 137– 43. Google Scholar CrossRef Search ADS PubMed  20 Apisarnthanarak A, Yatrasert A, Mundy LM; Thammasat University Antimicrobial Stewardship Team. Impact of education and an antifungal stewardship program for candidiasis at a Thai tertiary care center. Infect Control Hosp Epidemiol  2010; 31: 722– 7. Google Scholar CrossRef Search ADS PubMed  21 Cook PP, Gooch M. Long-term effects of an antimicrobial stewardship programme at a tertiary-care teaching hospital. Int J Antimicrob Agents  2015; 45: 262– 7. Google Scholar CrossRef Search ADS PubMed  22 Standiford HC, Chan S, Tripoli M et al.   Antimicrobial stewardship at a large tertiary care academic medical center: cost analysis before, during, and after a 7-year program. Infect Control Hosp Epidemiol  2012; 33: 338– 45. Google Scholar CrossRef Search ADS PubMed  23 Reed EE, West JE, Keating EA et al.   Improving the management of candidemia through antimicrobial stewardship interventions. Diagn Microbiol Infect Dis  2014; 78: 157– 61. Google Scholar CrossRef Search ADS PubMed  24 Alfandari S, Berthon C, Coiteux V. Antifungal stewardship: implementation in a French teaching hospital. Med Mal Infect  2014; 44: 154– 8. Google Scholar CrossRef Search ADS PubMed  25 Valerio M, Muñoz P, Rodríguez CG et al.   Antifungal stewardship in a tertiary-care institution: a bedside intervention. Clin Microbiol Infect  2015; 21: 492.e1– 9. Google Scholar CrossRef Search ADS   26 López-Medrano F, San Juan R, Lizasoain M et al.   A non-compulsory stewardship programme for the management of antifungals in a university-affiliated hospital. Clin Microbiol Infect  2013; 19: 56– 61. Google Scholar CrossRef Search ADS PubMed  27 Ramos A, Pérez-Velilla C, Asensio A et al.   Antifungal stewardship in a tertiary hospital. Rev Iberoam Micol  2015; 32: 209– 13. Google Scholar CrossRef Search ADS PubMed  28 Mondain V, Lieutier F, Hasseine L et al.   A 6-year antifungal stewardship programme in a teaching hospital. Infection  2013; 41: 621– 8. Google Scholar CrossRef Search ADS PubMed  29 Micallef C, Aliyu SH, Santos R et al.   Introduction of an antifungal stewardship programme targeting high-cost antifungals at a tertiary hospital in Cambridge, England. J Antimicrob Chemother  2015; 70: 1908– 11. Google Scholar PubMed  30 Marzolini MAV, Thomson KJ, Peggs KS. Antifungal stewardship: towards defining safe stopping criteria for therapeutic oral azoles. Br J Haematol  2016; 172: 285– 7. Google Scholar CrossRef Search ADS PubMed  31 Guarascio AJ, Slain D, McKnight R et al.   A matched-control evaluation of an antifungal bundle in the intensive care unit at a university teaching hospital. Int J Clin Pharm  2013; 35: 145– 8. Google Scholar CrossRef Search ADS PubMed  32 Agrawal S, Barnes R, Brüggemann RJ et al.   The role of the multidisciplinary team in antifungal stewardship. J Antimicrob Chemother  2016; 71: ii37– 42. Google Scholar CrossRef Search ADS PubMed  33 Bryant PA; Australasian Stewardship of Antimicrobials in Paediatrics group. Antimicrobial stewardship resources and activities for children in tertiary hospitals in Australasia: a comprehensive survey. Med J Aust  2015; 202: 134– 8. Google Scholar CrossRef Search ADS PubMed  34 Cappelletty D, Jacobs D. Evaluating the impact of a pharmacist’s absence from an antimicrobial stewardship team. Am J Health Syst Pharm  2013; 70: 1065– 9. Google Scholar CrossRef Search ADS PubMed  35 Goff DA, Jankowski C, Tenover FC. Using rapid diagnostic tests to optimize antimicrobial selection in antimicrobial stewardship programs. Pharmacotherapy  2012; 32: 677– 87. Google Scholar CrossRef Search ADS PubMed  36 Denning DW, Perlin DS, Muldoon EG et al.   Delivering on antimicrobial resistance agenda not possible without improving fungal diagnostic capabilities. Emerg Infect Dis  2017; 23: 177– 83. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

A systematic review of interventions and performance measures for antifungal stewardship programmes

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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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0305-7453
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1460-2091
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10.1093/jac/dkx388
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Abstract

Abstract Objectives Antifungal resistance is a significant and emerging threat. Stewardship programmes (SPs) have been proposed as an opportunity to optimize antifungal use. While examples of antifungal SP implementation have been recently described, there is yet to be an overview of interventions and their impacts on performance measures. Methods We systematically reviewed published articles using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses check-list 2009. MEDLINE was searched using the term ‘antifungal stewardship’ on 15 February 2017. Eligible studies were those that described an antifungal SP and included an intervention and an evaluation of performance measures. Results A total of 97 studies were identified and 14 were included. Only five studies reported an antifungal stewardship team composed of all the recommended members. The main intervention was the formulation of recommendations to change treatment (12 of 14). The main performance measure collected was antifungal consumption (10 of 14), followed by antifungal expenditure (7 of 14), adherence to therapeutic advice (4 of 14) and impact on mortality (4 of 14). Antifungal consumption was reduced by 11.8% to 71% and antifungal expenditure by as much as 50%. Adherence to therapeutic advice ranged from 40% to 88%, whereas antifungal SPs had no impact on mortality. Conclusions All antifungal SPs had an impact, in particular on antifungal consumption and antifungal expenditure. Active intervention including a review of prescriptions seems to have more impact than implementation of treatment guidelines only. According to available published studies, antifungal consumption appears to be the most achievable performance measure to evaluate the impact of an antifungal SP. Introduction Antimicrobial resistance is a major public health concern and is identified by the WHO as one of the three greatest threats to human health.1 The development of resistance is related to excessive use of antimicrobial drugs. In this context, antibiotic stewardship programmes (SPs) have been proposed as an opportunity to contain antimicrobial resistance.2,3 They are supported by guidelines published by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America.4,5 The benefits of antibiotic SP are well-known and include improved patient outcomes, reduction of adverse events including Clostridium difficile infections, reduction in antibiotic resistance and optimization of resource consumption.4,5 Resistance concerns are not limited to antibacterials as antifungal resistance is also a significant and emerging threat, mainly to azoles for Candida and Aspergillus: resistance rates were reported between 11.9% and 14% for Candida glabrata and over 2.3% for Aspergillus fumigatus, with higher rates in some regions reflecting disparities in microbiological procedures to detect resistance.6 As demonstrated for antibiotics, inappropriate antifungal use contributes to an increase in resistance, mortality, morbidity and costs.7 While antibiotic SPs are widely implemented,8 few implementations of antifungal SPs have been reported in the literature. Antifungal SP is defined as an optimal use of antifungals through careful selection of agents based on patient profile, target organism, toxicity, cost, as well as the likelihood of emergence and spread of antifungal resistance.9 Antifungal SP initiatives aim to improve outcomes, avoid adverse drug-related effects, reduce emergence of resistance, more rapidly diagnose the fungal agent and control costs.7 While antifungal SP implementation has been recently described in reviews of the literature,7,9–15 there is yet to be an overview of interventions and their impact on performance measures. The objective of this study was therefore to analyse systematically the antifungal SP studies to describe interventions and their impact on performance measures. Methods Eligibility criteria Studies that described an antifungal SP and included an intervention and a performance measure were eligible; reviews, non-interventional studies, as well as those not written in English, were excluded. Search and information sources MEDLINE was searched using the term ‘antifungal stewardship’ (Search details: ‘antifungal agents’[Pharmacological Action] OR ‘antifungal agents’[MeSH Terms] OR (‘antifungal’[All Fields] AND ‘agents’[All Fields]) OR ‘antifungal agents’[All Fields] OR ‘antifungal’[All Fields]) AND stewardship [All Fields]). No filter or date limitation was used; the last search was performed on 15 February 2017. Study selection After screening the 97 records for duplicates, abstracts were uploaded in MEDLINE to assess eligibility of articles. If the abstract was not informative to assess eligibility, full texts were retrieved from the university library. To increase the completeness of the search, a snowballing approach was used: references of eligible articles and pertinent reviews were scanned.16 To resolve disagreement for inclusion, full-text articles were read in full independently by two investigators (A. L. B. and G. L.) leading to a consensus after discussion. Data extraction The full texts of the included articles were retrieved from the university library. Information about context, objectives, number of patients or reviewed prescriptions, interventions and performance measures [antifungal use, adherence to therapeutic advice, quality of care, mortality, incidence of invasive fungal infection (IFI)] was extracted after each included full-text article was read in full. To ensure reproducibility and completeness of data extraction, an Excel spreadsheet (Microsoft Corp., Redmond, WA, USA) compiling all variables to be extracted was used. Data extraction was double-checked by A. L. B. and G. L. Disagreements over data extraction were resolved by discussion. Data were centrally checked by an independent operator for completeness, plausibility and integrity before synthesis. Synthesis of results and summary measures The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) check-list 2009 was used as a methodological support of the systematic review.17 A narrative synthesis approach was used to summarize data extracted from full-text articles. Results A total of 97 records were identified; one record18 was identified using a snowballing approach. Among the 97 records, 64 did not describe an antifungal SP and were excluded. Among the 33 full texts assessed, 16 were antifungal SP reviews, two were non-interventional studies and one was not written in English; these articles were excluded. Thus, 14 studies were eligible for systematic review (Figure 1). Figure 1. View largeDownload slide PRISMA flow diagram mapping out the number of records identified, included and excluded, and the reasons for exclusions. Figure 1. View largeDownload slide PRISMA flow diagram mapping out the number of records identified, included and excluded, and the reasons for exclusions. Half of the studies were published in 2014 or later. The first study describing an antifungal SP with an intervention was published in 2009; its objective was to evaluate the impact of implementing practice guidelines for antifungal therapy in a surgical intensive care unit on the use and cost of antifungals.18 Three (of 14) studies19–21 were specifically dedicated to candidaemia, and 1 (of 14)22 also included data on antibiotic SP. Nine of 14 studies were conducted in tertiary care hospitals, and five in university hospitals (Table 1). To collect information about the initiation of antifungal treatment, most studies (10 of 12) used pharmacy data, one study used microbiology data23 and one study was based on regular visits to a haematology unit24 (Table 1). Table 1 . Description of studies included in the systematic review Reference  Context/team  Objectives/method or request handling  Antifungals  Study period  Number of patients or prescriptions  Swoboda et al. (2009)18  University hospital, Heidelberg, Germany  To outline the impact of a standardized practice for ATF treatments  AmB, CAS, FLC, ITC, LAmB, POS, VRC  2005–07. 18 months before and 18 months after implementation of guidelines  Unreported  Team = not applicable (no review of prescriptions)  Method = practice guidelines imposed by the consultant responsible for ATF strategies and the head of intensive care unit  Apisarnthanarak et al. (2010)20  Thammasat University hospital, tertiary hospital, 350 beds, Pratumthani, Thailand  To evaluate the impact of education and ATF SP on prescribing practices, ATF consumption, Candida species infection and cost  CAS, FLC, ITC, LAmB, VRC  2006–08. 1.5 years before and 1.5 years after the implementation of ATF SP  1106 patients  Team = 3 members  Request handling = ATF prescription  López-Medrano et al. (2013)26  University-affiliated Hospital 12 de Octubre, Madrid, Spain  To review prescriptions and make non-compulsory recommendations  CAS, LAmB, VRC  2008–09. 24 months  662 prescriptions  Team = 3 members  Request handling = all ATF prescriptions checked every working day from the computerized system of the pharmacy  Standiford et al. (2012)22  Tertiary care academic medical centre, Baltimore, USA  To evaluate the cost before, during and after the programme  All antimicrobials including ABLC, AmB, CAS, FLC, LAmB, MIC, VRC  2001–10. 2001 before implementation/2002–08 during implementation/2009–10 after implementation  Unreported  Team = ID specialist and pharmacist  Request handling = antimicrobial orders  Antworth et al. (2013)19  Academic Hospital, 930 beds, Michigan, USA  To analyse the impact of a care bundle by antimicrobial stewardship team on the management of candidaemia  Candins, LAmB, POS, VRC  2010–11. 7 months non-interventional/7 months interventional  78 patients  Team = ID specialist and pharmacist  Request handling = real-time surveillance of clinical decision support software  Guarascio et al. (2013)31  University Hospital, 450 beds, TN, USA  To evaluate utility of ATF bundle in limiting excessive use of echinocandins in intensive care unit  CAS  6 months  108 patients  Team = pharmacist  Request handling = prescription of caspofungin  Mondain et al. (2013)28  Teaching tertiary care hospital, 1800 beds, Nice, France  To describe and assess ATF SP impact on ATF prescriptions and their costs  Candins, LAmB, POS, VRC  2005–10. 5 years  636 prescriptions  Team = ID specialist and pharmacist  Request handling = ATF prescription  Alfandari et al. (2014)24  University Hospital, Lille, France  To implement ATF SP  CAS, LAmB, VRC  2009–10. 24 months  192 patients  Team = ID specialist  Request handling = visit of haematology unit twice a week  Reed et al. (2014)23  Teaching Hospital, 1229 beds, OH, USA  To evaluate impact of ATF SP pharmacist’s intervention on time to effective ATF, in-hospital mortality, infections, length of stay and costs  ABLC, AmB, CAS, FLC  2008 and 2010. 1 year 2008 compared with 1 year 2010  173 patients  Team = 3 members  Request handling = microbiology laboratory notification of a yeast to the pharmacist and electronic list of patients with Candida positive blood culture  Ramos et al. (2015)27  Tertiary Hospital Puerta de Hierro, Madrid, Spain  To evaluate efficiency of ASP  Candins, LAmB, VRC  Oct 2012–May 2013. 8 months  280 prescriptions  Team = 3 members  Request handling = electronic medical record including prescriptions and progress notes  Valerio et al. (2015)25  Tertiary Hospital, Gregorio Maranon, Madrid, Spain  To describe a bedside non-restrictive ATF SP and evaluate its economic impact  Candins, LAmB, POS, VRC  Oct 2010–Sept 2012. 12 months non-interventional/12 months interventional  453 patients  Team = 3 members  Request handling = non-compulsory computerized physician order, which alerts pharmacist of a new ATF prescription  Micallef et al. (2015)29  Tertiary referral Hospital, Cambridge, England  To conduct an observational prospective study by an ASP team targeting the use of ATFs  CAS, LAmB, MIC, VRC  July 2013–June 2014. 12 months  173 patients  Team = pharmacist and microbiologist  Request handling = interrogation of the pharmacy system on systemic ATFs  Cook and Gooch (2015)21  Tertiary care teaching Hospital, 904 beds, Greenville, USA  To evaluate the impact of an antimicrobial stewardship on antimicrobial use including ATF  ABLC, MIC, POS, VRC  2001–13. 13 years  Unreported  Team = ID specialist and pharmacist  Request handling = computer-generated report of all patients receiving controlled and restricted drugs  Marzolini et al. (2016)30  University College London Cancer Institute, London, UK  To evaluate compliance and safety of a modified guideline incorporating direction for the cessation of ATF to decrease expenditure of POS  POS  June 2012–July 2014. 24 months  42 patients  Team = not applicable (no review of prescriptions)  Method = retrospective study of conversion to POS  Reference  Context/team  Objectives/method or request handling  Antifungals  Study period  Number of patients or prescriptions  Swoboda et al. (2009)18  University hospital, Heidelberg, Germany  To outline the impact of a standardized practice for ATF treatments  AmB, CAS, FLC, ITC, LAmB, POS, VRC  2005–07. 18 months before and 18 months after implementation of guidelines  Unreported  Team = not applicable (no review of prescriptions)  Method = practice guidelines imposed by the consultant responsible for ATF strategies and the head of intensive care unit  Apisarnthanarak et al. (2010)20  Thammasat University hospital, tertiary hospital, 350 beds, Pratumthani, Thailand  To evaluate the impact of education and ATF SP on prescribing practices, ATF consumption, Candida species infection and cost  CAS, FLC, ITC, LAmB, VRC  2006–08. 1.5 years before and 1.5 years after the implementation of ATF SP  1106 patients  Team = 3 members  Request handling = ATF prescription  López-Medrano et al. (2013)26  University-affiliated Hospital 12 de Octubre, Madrid, Spain  To review prescriptions and make non-compulsory recommendations  CAS, LAmB, VRC  2008–09. 24 months  662 prescriptions  Team = 3 members  Request handling = all ATF prescriptions checked every working day from the computerized system of the pharmacy  Standiford et al. (2012)22  Tertiary care academic medical centre, Baltimore, USA  To evaluate the cost before, during and after the programme  All antimicrobials including ABLC, AmB, CAS, FLC, LAmB, MIC, VRC  2001–10. 2001 before implementation/2002–08 during implementation/2009–10 after implementation  Unreported  Team = ID specialist and pharmacist  Request handling = antimicrobial orders  Antworth et al. (2013)19  Academic Hospital, 930 beds, Michigan, USA  To analyse the impact of a care bundle by antimicrobial stewardship team on the management of candidaemia  Candins, LAmB, POS, VRC  2010–11. 7 months non-interventional/7 months interventional  78 patients  Team = ID specialist and pharmacist  Request handling = real-time surveillance of clinical decision support software  Guarascio et al. (2013)31  University Hospital, 450 beds, TN, USA  To evaluate utility of ATF bundle in limiting excessive use of echinocandins in intensive care unit  CAS  6 months  108 patients  Team = pharmacist  Request handling = prescription of caspofungin  Mondain et al. (2013)28  Teaching tertiary care hospital, 1800 beds, Nice, France  To describe and assess ATF SP impact on ATF prescriptions and their costs  Candins, LAmB, POS, VRC  2005–10. 5 years  636 prescriptions  Team = ID specialist and pharmacist  Request handling = ATF prescription  Alfandari et al. (2014)24  University Hospital, Lille, France  To implement ATF SP  CAS, LAmB, VRC  2009–10. 24 months  192 patients  Team = ID specialist  Request handling = visit of haematology unit twice a week  Reed et al. (2014)23  Teaching Hospital, 1229 beds, OH, USA  To evaluate impact of ATF SP pharmacist’s intervention on time to effective ATF, in-hospital mortality, infections, length of stay and costs  ABLC, AmB, CAS, FLC  2008 and 2010. 1 year 2008 compared with 1 year 2010  173 patients  Team = 3 members  Request handling = microbiology laboratory notification of a yeast to the pharmacist and electronic list of patients with Candida positive blood culture  Ramos et al. (2015)27  Tertiary Hospital Puerta de Hierro, Madrid, Spain  To evaluate efficiency of ASP  Candins, LAmB, VRC  Oct 2012–May 2013. 8 months  280 prescriptions  Team = 3 members  Request handling = electronic medical record including prescriptions and progress notes  Valerio et al. (2015)25  Tertiary Hospital, Gregorio Maranon, Madrid, Spain  To describe a bedside non-restrictive ATF SP and evaluate its economic impact  Candins, LAmB, POS, VRC  Oct 2010–Sept 2012. 12 months non-interventional/12 months interventional  453 patients  Team = 3 members  Request handling = non-compulsory computerized physician order, which alerts pharmacist of a new ATF prescription  Micallef et al. (2015)29  Tertiary referral Hospital, Cambridge, England  To conduct an observational prospective study by an ASP team targeting the use of ATFs  CAS, LAmB, MIC, VRC  July 2013–June 2014. 12 months  173 patients  Team = pharmacist and microbiologist  Request handling = interrogation of the pharmacy system on systemic ATFs  Cook and Gooch (2015)21  Tertiary care teaching Hospital, 904 beds, Greenville, USA  To evaluate the impact of an antimicrobial stewardship on antimicrobial use including ATF  ABLC, MIC, POS, VRC  2001–13. 13 years  Unreported  Team = ID specialist and pharmacist  Request handling = computer-generated report of all patients receiving controlled and restricted drugs  Marzolini et al. (2016)30  University College London Cancer Institute, London, UK  To evaluate compliance and safety of a modified guideline incorporating direction for the cessation of ATF to decrease expenditure of POS  POS  June 2012–July 2014. 24 months  42 patients  Team = not applicable (no review of prescriptions)  Method = retrospective study of conversion to POS  ABLC, amphotericin B lipid complex; AmB, amphotericin B desoxycholate; ASP, antifungal stewardship; ATF, antifungal; CAS, caspofungin; FLC, fluconazole; ITC, itraconazole; LAmB, liposomal amphotericin B; MIC, micafungin; POS, posaconazole; VRC, voriconazole. The objective of the studies was to evaluate the impact on antifungal use of a review of prescription (12 of 14) or implementation of practice guidelines (2 of 14). The study period ranged from 6 months to 13 years (Table 1); the median study duration was 1 year. Five studies incorporated a non-interventional period considered as a control period that doubles the time of the study (Table 1).18–20,23,25 Among the 12 studies that included a review of prescriptions, only five reported an antifungal stewardship team composed of all the recommended members [i.e. an infectious disease (ID) specialist, a clinical pharmacist and a clinical microbiologist];20,23,25–27 four lacked a clinical microbiologist,19,21,22,28 one lacked an ID specialist,29 one lacked an ID specialist and a clinical microbiologist,24 and one lacked a clinical microbiologist and a clinical pharmacist.24 All studies (n = 12) included in their review of prescriptions echinocandins, liposomal or lipid complex amphotericin B, voriconazole and posaconazole. Two studies also included fluconazole18,20 and two studies included fluconazole and itraconazole18,20 (Table 1). A mean of 258 patients (range 42–1106) were included in the studies (n = 9) and a mean of 526 (range 280–662) prescriptions were reviewed (n = 3); the number of patients and prescriptions were not reported for two studies.18,22 Among studies in which all core members were represented in the antifungal stewardship team (n = 5), a mean of 577 patients (range 453–1106) were reviewed, and in studies in which the team lacked at least one member (n = 7), a mean of 137 patients (range 78–192) were reviewed. Among the 14 articles included in the present review, the most frequent intervention was the formulation of recommendations to change treatment (12 of 14; Table 2). In the majority of studies (10 of 14), the recommendations were formulated directly to the clinician in charge of the patient, and in the remaining studies (2 of 14), the recommendations were included in an electronic medical record.21,27 In two (of 14) studies, the only intervention was the implementation of practice guidelines.18,30 A minimum of three performance measures were collected in half of the studies including a review of prescription (6 of 12). Among the studies with a complete stewardship team (n = 5), more than three performance measures were collected, and in studies with an incomplete stewardship team, one (1 of 7) or two (5 of 7) measures were collected (Table 2). Table 2. Description of interventions and performance measures used in the studies included in the review References  Interventions  Performance measures   antifungal use  cost  adherence to therapeutic advice  quality of care  mortality  incidence of IFI  other  Swoboda et al. (2009)18  Implementation of practice guidelines  ↓ >50%  ↓ 50%            Apisarnthanarak et al. (2010)20  Education, ATF hepatic and renal adjustment tool, ATF prescription form, bedside case management  ↓ 59%, ↓ 51.6% DDD (FLC)  $31615          ↓ 47% inappropriate ATF, C. glabrata and krusei incidence, ↑ C. albicans incidence  López-Medrano et al. (2013)26  Recommendation to change treatment personally discussed with the clinician  ↓ DDD (VRC 31.4%, CAS 20.2%)  ↓ 11.8%    No reduction, no increase in persistent candidaemia  No increase  No increase  No increase in fluconazole-resistant Candida  Standiford et al. (2012)22  Active computer real-time review, active intervention when necessary    ↓ 45.8%            Antworth et al. (2013)19  Education on candidaemia management, recommendations on appropriate ATF and duration, removal of catheter, request for repeat blood culture and ophthalmological examination, encourage ID consultation if necessary  Fewer excess days of therapy (5 vs 83 days)      Rate of persistent or recurrent candidaemia similar, LOS similar, time until clearance of candidaemia similar      ↑ 21.9% ophthalmological examination, ↑ 13.5% appropriate ATF, ↑ 29.9% appropriate duration  Guarascio et al. (2013)31  Assist clinicians with ongoing awareness and reassessment of treatment plans at critical points during therapy  ↓ days of CAS (2 days)  $1013 per patient            Mondain et al. (2013)28  Post-prescription review during a weekly meeting, antimicrobial order form set-up, emergency tomodensitometry, on-site TDM for VRC and POS, diagnostic tool availability      88%  Improvement        Alfandari et al. (2014)24  Discussion of prescriptions, telephone counselling, training meetings, draft guidelines  ↓ 40%          Stable    Reed et al. (2014)23  Candidaemia guideline development, recommendations by the pharmacist for initiation of ATF, ID and ophthalmology consult, CVC removal, de-escalation, IV to oral conversion    Similar hospital cost    Similar LOS  Similar    ↓ 12.2 h time to effective therapy  Ramos et al. (2015)27  Programmed review of restricted ATFs, recommendation in the electronic medical record  ↓ 42%    40%    Similar      Valerio et al. (2015)25  Therapeutic recommendations by an ID specialist  ↓ DDD 17%  ↓ 21.7%      Similar  No reduction    Micallef et al. (2015)29  Clinical advice    ↓ 9.7%  50%          Cook and Gooch (2015)21  Review of prescriptions, prior approval for restricted antimicrobials, recommendations by electronic support  ↓ 71%    Increase of 9.2%          Marzolini et al. (2016)30  Adoption of a modified guideline              98% compliance to guideline  References  Interventions  Performance measures   antifungal use  cost  adherence to therapeutic advice  quality of care  mortality  incidence of IFI  other  Swoboda et al. (2009)18  Implementation of practice guidelines  ↓ >50%  ↓ 50%            Apisarnthanarak et al. (2010)20  Education, ATF hepatic and renal adjustment tool, ATF prescription form, bedside case management  ↓ 59%, ↓ 51.6% DDD (FLC)  $31615          ↓ 47% inappropriate ATF, C. glabrata and krusei incidence, ↑ C. albicans incidence  López-Medrano et al. (2013)26  Recommendation to change treatment personally discussed with the clinician  ↓ DDD (VRC 31.4%, CAS 20.2%)  ↓ 11.8%    No reduction, no increase in persistent candidaemia  No increase  No increase  No increase in fluconazole-resistant Candida  Standiford et al. (2012)22  Active computer real-time review, active intervention when necessary    ↓ 45.8%            Antworth et al. (2013)19  Education on candidaemia management, recommendations on appropriate ATF and duration, removal of catheter, request for repeat blood culture and ophthalmological examination, encourage ID consultation if necessary  Fewer excess days of therapy (5 vs 83 days)      Rate of persistent or recurrent candidaemia similar, LOS similar, time until clearance of candidaemia similar      ↑ 21.9% ophthalmological examination, ↑ 13.5% appropriate ATF, ↑ 29.9% appropriate duration  Guarascio et al. (2013)31  Assist clinicians with ongoing awareness and reassessment of treatment plans at critical points during therapy  ↓ days of CAS (2 days)  $1013 per patient            Mondain et al. (2013)28  Post-prescription review during a weekly meeting, antimicrobial order form set-up, emergency tomodensitometry, on-site TDM for VRC and POS, diagnostic tool availability      88%  Improvement        Alfandari et al. (2014)24  Discussion of prescriptions, telephone counselling, training meetings, draft guidelines  ↓ 40%          Stable    Reed et al. (2014)23  Candidaemia guideline development, recommendations by the pharmacist for initiation of ATF, ID and ophthalmology consult, CVC removal, de-escalation, IV to oral conversion    Similar hospital cost    Similar LOS  Similar    ↓ 12.2 h time to effective therapy  Ramos et al. (2015)27  Programmed review of restricted ATFs, recommendation in the electronic medical record  ↓ 42%    40%    Similar      Valerio et al. (2015)25  Therapeutic recommendations by an ID specialist  ↓ DDD 17%  ↓ 21.7%      Similar  No reduction    Micallef et al. (2015)29  Clinical advice    ↓ 9.7%  50%          Cook and Gooch (2015)21  Review of prescriptions, prior approval for restricted antimicrobials, recommendations by electronic support  ↓ 71%    Increase of 9.2%          Marzolini et al. (2016)30  Adoption of a modified guideline              98% compliance to guideline  ATF, antifungal; CAS, caspofungin; CVC, central venous catheter; FLC, fluconazole; IV, intravenous; LOS, length of stay; POS, posaconazole; VRC, voriconazole; TDM, therapeutic drug monitoring. The most frequent performance measure collected was antifungal consumption (10 of 14): reduction in consumption ranged from 11.8% to 71%, and reduction in DDD ranged from 17% to 52% (3 of 14). A reduction of 2 days of therapy was reported from one study.31 A reduction of antifungal cost was found in half of the studies (7 of 14), and cost containment was reported in one study.23 A decrease of 50% in antifungal use and >50% in antifungal cost was reported in one of the two studies based on implementation of treatment guidelines only (Table 2).18 Adherence to therapeutic advice was evaluated in four of the 12 studies that included a review of prescription and ranged from 40% to 88%. Among these, one study used an electronic medical record and found 40% adherence.27 The impact of antifungal SP in terms of mortality was evaluated in 4 of 14 studies, and in terms of IFI incidence in 3 of 14 studies. From these studies, no impact on mortality or on IFI incidence was observed. Conversely, one of the four studies that investigated quality of care found an improvement in this measure. Other performance measures were reported, e.g. the proportion of appropriate prescriptions20 and time to effective therapy,23 which were improved by antifungal SPs. For studies focusing on candidaemia,19–21 incidences of Candida krusei, C. glabrata, and Candida albicans were evaluated, as was the time to clearance of candidaemia and rate of ophthalmological examinations. Antifungal SPs had a positive impact on the rate of resistant Candida20 and ophthalmological examinations19 (Table 2). Discussion Antifungal stewardship is a recent matter of debate, which is illustrated by the publication date of the included studies, the majority of which were published from 2014. It was found from this review that antifungal SPs were implemented in tertiary care hospitals or university hospitals, which can be explained by the frequent use of these drugs in critically ill patients admitted to such healthcare structures, as well as the availability of human resources and facilities required to implement antifungal SP.8 The role of the multidisciplinary team to ensure optimal management of IFI is unquestionable.32 It should include ID specialists, a clinical pharmacist and a clinical microbiologist.7 However, among the 12 articles including a review of prescription, only five articles reported a complete antifungal stewardship team. An information system specialist, infection control professional and hospital epidemiologist are also included in the antibiotic SP team according to IDSA guidelines.5 It is of note that none of the included studies had a stewardship team that included such healthcare professionals and the recommendations for antifungal SP do not stipulate the inclusion of these. Interestingly, among the studies included herein, the number of prescriptions reviewed and performance measures collected were greater if the antifungal stewardship team was complete, which suggests more extensive investigations are performed when the required human resources are allocated to the SP. This is in accordance with a review describing Australasian resources and activities for antimicrobial SP from which it appears that a lack of personnel involved in SP was a barrier to successful antimicrobial SP.33 Furthermore, it has been suggested that the absence of a pharmacist is associated with an increased rate of inappropriate antimicrobial use and an increased duration of treatment.34 However, it is not possible to comment further on this aspect from the studies included herein; only one study did not include a pharmacist, and furthermore did not report on these parameters.24 The most frequent intervention was the formulation of recommendations to change treatment. According to Muñoz et al.,12 formulation of therapeutic advice is part of the persuasive interventions that require more time and effort, but which have long-term acceptance. In one of the two studies only based on implementation of guidelines,35 authors obtained an impact on antifungal consumption and cost, but it is not indicated if the action was sustainable or not. An interesting future development in antifungal SP may be the use of rapid diagnostic tests, including Candida molecular diagnostic techniques, which have been proposed by Goff et al.35 and Denning et al.36 to optimize antimicrobial selection, control antimicrobial resistance and improve clinical outcome; to our knowledge, the impact of this intervention through an antifungal SP has yet to be evaluated. Muñoz et al.12 also noted that indicators are mandatory for antifungal SP. Two types of indicators are required: process measures, and outcome measures.10 This has been further detailed by Ananda-Rajah et al.11 who published a detailed list of performance measures for antifungal SP: process measures include antifungal drug consumption, minimum standards of prescribing, therapeutic streamlining, timeliness and completeness of diagnostic investigations when IFI is suspected, and concordance of prescribing with institutional guidelines; outcome measures include IFI incidence in targeted groups and antifungal drug expenditure. Moreover, Ananda-Rajah et al.11 created a specific performance measure for antifungal SP named ‘structural measures’ that include an antifungal drug policy and locally adapted practice guidelines. Conversely, bundle of care indicators in patients with candidaemia were specifically developed by Miyazaki and Kohno13 and extensively reviewed by Pfaller and Castanheira14 and Ruhnke15 Interestingly, all types of performance measures were collected in the 14 studies included in the present review. It has to be noted that only a few studies evaluated the impact of antifungal SP on IFI incidence and mortality, as a good indication of quality of care: this is in accordance with IDSA guidelines that consider measurement of antibiotic SP impact on outcome more challenging than measuring antibiotic use or guideline compliance.5 The most frequent process measure was antifungal consumption using DDD. According to IDSA guidelines, days of therapy are preferred because they are not impacted by dose adjustments and can be used in paediatrics when weight-based dosing is required. However, DDDs remain an alternative if patient-level antimicrobial use data cannot be obtained.5 The second most frequent process measure collected was the agreement of prescribing with treatment guidelines. Near perfect agreement was obtained in an antifungal SP that was only based on implementation of modified guidelines.30 The level of adherence to therapeutic advice was also evaluated in four studies and it is of note that the lowest adherence was obtained using an electronic medical record to formulate therapeutic advice;27 direct interactions with the clinicians in charge of the patient seem more efficient to obtain better compliance.28 The most frequent outcome measure (reported in half of included studies) was antifungal expenditure; although cost is considered to be a secondary goal for antimicrobial stewardship, cost saving is one way to justify continued administrative support for antimicrobial SP activities.5 All studies included herein focused on high-cost antifungals and only a few also included fluconazole and itraconazole.18,20,22,23 It could, however, be of interest to study fluconazole resistance, as the potential of fluconazole to induce resistance in Candida is high. However, it has to be noted that resistance as an indicator of SP is considered by IDSA guidelines to be a very complex metric because resistance development and spread is multifactorial.5 In antifungal SP, only two studies evaluated Candida resistance;20,26 one reported a lower level of resistant Candida after an antifungal SP implementation.20 Length of hospitalization, days of hospitalization avoided, as well as parenteral therapy and days of central venous access avoided, are preferred metrics for antibiotic SP because it is a consequence of therapeutic streamlining.5 From the 14 studies, only two related to candidaemia evaluated the length of hospitalization that remained unchanged despite antifungal SP. Surprisingly, among the outcome measures reported in the included studies, occurrence of adverse events was not used. The main limitation of this systematic review is the low number of research papers on the topic. Incomplete retrieval is possible for papers outside MEDLINE. Conclusions All antifungal SPs included in this systematic review had an impact on antifungal prescription, in particular on antifungal consumption and antifungal expenditure. The multidisciplinary team, as well as face-to-face discussion about antifungal prescription, appear to be cornerstones of antifungal SP. A future direction could be the development of guidelines for antifungal SP implementation, as is currently the case for antibiotics. Acknowledgements We thank Philip Robinson (DRCI, Hospices Civils de Lyon) for his helpful comments. Funding This study was carried out as part of our routine work. Transparency declarations Nothing to declare. Author contributions A. L. B. conceived the project, collated the search results, reviewed data in PRISMA format, drafted, compiled and approved the final report. L. A., E. J., V. P. and T. R. reviewed data, edited the manuscript and approved the final report.  F. A., J. L. F. and C. G. reviewed data and approved the final report. C. C. conceived the project and approved the final report. G. L. conceived the project, reviewed data and approved the final report. Data sharing The full dataset is available from the corresponding author. References 1 McLoughlin H. Conference report from International Congress on Infectious Diseases 2014: part 2. Future Microbiol  2014; 9: 1299– 301. Google Scholar CrossRef Search ADS PubMed  2 Verweij P, Lyon S. Optimizing antifungal strategies to improve patient survival. Future Microbiol  2016; doi:10.2217/fmb-2016-0153. 3 Laxminarayan R, Duse A, Wattal C et al.   Antibiotic resistance-the need for global solutions. Lancet Infect Dis  2013; 13: 1057– 98. Google Scholar CrossRef Search ADS PubMed  4 Barlam TF, Cosgrove SE, Abbo LM et al.   Implementing an Antibiotic Stewardship Program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis  2016; 62: e51– 77. 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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Feb 1, 2018

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