The Time for Antifungal Stewardship Programs Is Now

Invasive fungal infections are a significant cause of mortality and morbidity, particularly in immunocompromised patients with hematologic malignancies and hematopoietic stem cell recipients, as well as solid organ transplant recipients. In the United States, Candida accounts for the majority of cases of health care-associated bloodstream infections.^1,2 Even in light of newly available antifungal agents, the costs of antifungals are substantial, while the mortality for invasive aspergillosis and invasive candidiasis remains high.^3-7 Retrospective studies report that 30% to 50% of overall antifungal prescriptions were not optimized or inappropriate.^8,9 The rate of inappropriate antifungal prescribing is similar to that for antibiotics, demonstrating the alarming need for antifungal stewardship.¹ The role of stewardship may offer value to optimizing clinical outcomes while minimizing antifungal overuse and costs, therefore also controlling resistance developed from selection pressure. Other challenges of treating invasive fungal infections include rising drug resistance and delayed initiation of therapy due to the lack of rapid and accurate diagnostic tools.

The extent of knowledge and understanding about antimycotic resistance and drug-resistant fungal infections is still unclear. Particularly, infections caused by Candida auris are of recent serious concern because of the inherent multidrug resistance of the fungi pathogen, limiting therapeutic options.¹⁰ According to the Centers for Disease Control and Prevention (CDC) surveillance data, approximately 7% of all Candida bloodstream isolates were fluconazole resistant and mostly identified as Candida glabrata.^11,12 Additionally, echinocandin resistance in C. glabrata isolates has doubled from 4% in 2008 to 8% in 2014.¹³ Not only is antifungal resistance emerging with Candida species but it is also, more recently, increasing with Aspergillus species. Reported widespread azole resistance is also increasing in Aspergillus fumigatus, which was first documented in the Netherlands and is now seen in various regions of the world.¹⁴ Recent surveillance studies have identified azole resistance as a result of widespread environmental fungicide use.^15,16

Compared with antibiotic stewardship, published experience focusing on antifungal stewardship, as well as drug-resistant fungal pathogens, is sparse and limited but emerging. Nevertheless, rising bacterial and fungal resistance is an internationally recognized and public threat, leading to the increasing need for the implementation of antimicrobial stewardship as addressed by the newly effective Joint Commission standard for hospitals.¹⁷

Additionally, the CDC offers support that complements other existing guidelines pertaining to antimicrobial stewardship, such as the recent 2016 guidelines by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America.^18,19 The IDSA guideline recommendations regarding interventions for optimal antifungal use focus on immunocompromised patients, including those with hematologic malignancy or solid organ transplant.

Implementation and Impact of Antifungal Stewardship Programs

In parallel with the CDC core elements of antimicrobial stewardship, Muñoz and colleagues described 7 essential elements for antifungal stewardship.^18,20 Although limited studies exist, there are some that highlight an overall positive impact of antifungal stewardship and interventions. A 12-month prospective study in a British tertiary referral hospital either discontinued or changed nearly half of amphotericin B and echinocandin treatments after implementation of an antifungal stewardship on high-cost antifungals, leading to significant health care cost savings.²¹ Alternatively, a different stewardship approach may include interventions made on positive fungal cultures, which have shown various results on the impact on clinical outcomes, which may improve time to effective therapy,²² increase proportion of patients who receive an ophthalmologic examination,²³ or reduce 30-day mortality.²⁴

Challenges and Barriers to Antifungal Stewardship Programs

There are numerous challenges in early diagnosis and treatment of invasive fungal infections, requiring the expertise of a collaborative group of trained infectious diseases specialists, clinical microbiologists, and other specialists in main prescribing departments such as hematology and oncology.¹⁹ Microbiology labs at institutions may not be able to readily test and determine susceptibilities for fungal isolates. Therefore, clinicians are limited in distinguishing drug-resistant infections based only on clinical suspicion or comfort with de-escalating to narrower spectrum antifungals.

Within the IDSA guidelines, recommendations related to antifungal stewardship include interventions that incorporate nonculture-based fungal markers, candidemia-care bundles, and prospective audit and feedback, similar to antibiotic stewardship.¹⁹ Utilization of galactomannan, (1-3)-b-D-glucan, or fungal polymerase chain reaction has demonstrated effective and safe reductions in antifungal treatment in high-risk patients with hematological malignancies. In addition, b-D-glucan is currently being studied to assist stewardships in de-escalation of broad-spectrum antifungals in patients with severe sepsis or septic shock receiving treatment in a multicenter, prospective, open-label, randomized trial.²⁵ An example of other stewardship interventions includes implementation of candidemia-care bundles, which was associated with improved care such as increasing use of appropriate antifungal therapy and rates of ophthalmologic examinations.²⁶

Specifically, with antifungal stewardship, there are certain areas for interventions that may differ from antibiotic stewardship to reduce antifungal resistance and selection pressure. For example, appropriate indications for antifungal prophylaxis and treatment should be evidence-based and selected in clinical situations that are efficacious, while avoiding use where fungal or mold colonization may occur.²⁰ Only 55% of physicians were able to correctly differentiate between infection and colonization in a survey of 200 providers, including those from medicine, pediatrics, and surgery, implying that there is a need for education on appropriate antifungal use.²⁷ Both antimicrobial and antifungal stewardships prioritize education as a core element.^18,20 Pharmacists have an expertise in pharmacotherapy that is pertinent for effective therapeutic drug monitoring, especially in optimizing antifungals with pharmacokinetic variability.²⁸ However, there are also limitations in availability of laboratory assays and validated efficacy and safety data on drug monitoring.

Overall, there is a great need for establishing antifungal stewardships in institutions with significant antifungal use due to the growing resistance, substantial costs, and potential to optimize outcomes. This is a collaborative effort that requires the teamwork of specialists in dynamic areas among physicians, pharmacists, and microbiologists, at minimum. The success of antifungal stewardship is defined on institution-specific needs and the epidemiology of the hospital. Documented inappropriate use of antifungals warrants opportunities for improvement and education, as part of the core elements of stewardship. Opportunities include interventions requiring infectious diseases consultation for fungemia, candidemia-care bundles, appropriate use of diagnostic biomarkers, therapeutic drug monitoring, and retrospective audit and feedback.

Dr. Vu is a Clinical Assistant Professor at Chicago State University and is in clinical practice at Rush University Children's Hospital in Chicago, Illinois. She completed her PGY-2 residency in infectious diseases at Midwestern University Chicago College of Pharmacy. She is an active member of ACCP, IDSA, and SIDP.

References

1. Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of health care-associated infections. N Engl J Med. 2014;370(13):1198-1208. doi: 10.1056/NEJMoa1306801.
2. Morgan J, Meltzer MI, Plikaytis BD, et al. Excess mortality, hospital stay, and cost due to candidemia: a case-control study using data from population-basted candidemia surveillance. Infect Control Hosp Epidemiol. 2005;26(6):540-547. doi: 10.1086/502581.
3. Wisplinghoff H, Bischoff T, Tallent SM, et al. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004;39(3):309-317. doi: 10.1086/421946.
4. Gudlaugsson O, Gillespie S, Lee K, et al. Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis. 2003;37(9):1172-1177. doi: 10.1086/378745.
5. Pappas PG, Res JH, Lee J, et al. A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis. 2003;37(5):634-643. doi: 10.1086/376906.
6. Pfaller M, Neofytos D, Diekema D, et al. Epidemiology and outcomes of candidemia in 3648 patients: data from the Prospective Antifungal Therapy (PATH Alliance) registry, 2004-2008. Diagn Microbiol Infect Dis. 2012;74(4):323-331. doi: 10.1016/j.diagmicrobio.2012.10.003.
7. Pfaller MA, Moet GJ, Messer SA, et al. Candida bloodstream infections comparison of species distributions and antifungal resistance patterns in community-onset and nosocomial isolates in the SENTRY Antimicrobial Surveillance Program, 2008-2009. Antimicrob Agents Chemother. 2001;55(2):561-566. doi: 10.1128/AAC.01079-10.
8. Valerio M, Rodriguez-Gonzalez CG, Muñoz P, et al. Evaluation of antifungal use in a tertiary care institution: antifungal stewardship urgently needed. J Antimicrob Chemother. 2014;69(7):1993-1999. doi: 10.1093/jac/dku053.
9. Nivoix Y, Launoy A, Lutun P, et al. Adherence to recommendations for the use of antifungal agents in a tertiary care hospital. J Antimicrob Chemother. 2012;67(10):2506-2513. doi: 10.1093/jac/dks256.
10. Vallabhaneni S, Kallen A, Tsay S, et al. Investigation of the first seven reported cases of Candida auris, a globally emerging invasive, multidrug-resistant fungus — United States, May 2013–August 2016. MMRW Morb Mortal Wkly Rep. 2016 Nov 11; 65(44): 1234-1237.
11. Cleveland AA, Harrison LH, Farley MM, et al. Declining incidence of candidemia and the shifting epidemiology of Candida resistance in two US metropolitan areas, 2008-2013: results from population-based surveillance. PLoS ONE. 2015;10(3):e0120452. doi: 10.1371/journal.pone.0120452.
12. Lockhart SR, Iqbal N, Cleveland AA, et al. Species identification and antifungal susceptibility testing of Candida bloodstream isolates from population-based surveillance studies in two U.S. cities from 2008 to 2011. J Clin Microbiol. 2012;50(11):3435-3442. doi: 10.1128/JCM.01283-12.
13. Vallabhaneni S, Cleveland AA, Farley MM, et al. Epidemiology and risk factors for echinocandin nonsusceptible Candida glabrata bloodstream infections. Data from a large multisite population-based candidemia surveillance program, 2008-2014. Open Forum Infect Dis. 2015;2(4):ofv163. doi: 10.1093/ofid/ofv163.
14. Verweij PE, Chowdhary A, Melchers WJ, Meis JF. Azole resistance in Aspergillus fumigatus: can we retain the clinical use of mold-active antifungal azoles? Clin Infect Dis. 2016; 62(3):362-368. doi: 10.1093/cid/civ885.
15. Snelders E, L van der Lee HA, Kuijpers J, et al. Emergence of azole resistance in Aspergilus fumigatus and spread of a single resistance mechanism. PLoS Med. 2008;5(11):e219. doi: 10.1371/journal.pmed.0050219.
16. Camps SM, van der Linden JW, Li Y, et al. Rapid induction of multiple resistance mechanisms in Aspergillus fumigatus during azole therapy: a case study and review of the literature. Antimicrob Agents Chemother. 2012;56(1):10-16. doi: 10.1128/AAC.05088-11.
17. The Joint Commission. Approved: new antimicrobial stewardship standard. Joint Commission Perspectives. 2016;36(6):1-8. https://jointcommission.org/assets/1/6/New_Antimicrobial_Stewardship_Standard.pdf. Accessed May 20, 2017.
18. Core elements of hospital antibiotic stewardship programs. Centers for Disease Control and Prevention website. http://cdc.gov/getsmart/healthcare/implementation/core-elements.html. Accessed May 20, 2017.
19. 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(10):e51-e77. doi: 10.1093/cid/ciw118.
20. Munoz Muñoz P, Valerio M, Vena A, Bouza E. Antifungal stewardship in daily practice and health economic implications. Mycoses. 2015;58(suppl 2):14-25. doi: 10.1111/myc.12329.
21. Micallef C, Aliyu SH, Santos R, Brown NM, Rosembert D, Enoch DA. Introduction of an antifungal stewardship programme targeting high-cost antifungals at a tertiary hospital in Cambridge, England. J Antimicrob Chemother. 2015; 70(6): 1908-1911. doi: 10.1093/jac/dkv040.
22. Reed EE, West JE, Keating EA, et al. Improving the management of candidemia through antimicrobial stewardship interventions. Diagn Microbiol Infect Dis. 2014;78(2):157-161. doi: 10.1016/j.diagmicrobio.2013.11.012.
23. Jones T, Wilson D, Sarubbi C, et al. Impact of mandatory infectious diseases consultation on fungemia management at a large academic medical center. Open Forum Infect Dis. 2016;3(suppl 1):1036. doi: 10.1093/ofid/ofw172.739.
24. Ishikane M, Hayakawa K, Kutsuna S, et al. The clinical value of infectious disease consultation for patients with candidemia in a tertiary care hospital in Japan over a 12-year period. Open Forum Infect Dis. 2016;3(Suppl 1):1594. doi: 10.1093/ofid/ofw172.1294.
25. A B-D-glucan driven antifungal stewardship approach for invasive candidiasis. clinicaltrials.gov/show/NCT03090334. Updated March 30, 2017. Accessed May 28, 2017.
26. Antworth A, Collins CD, Kunapuli A, et al. Impact of an antimicrobial stewardship program comprehensive care bundle on management of candidemia. Pharmacotherapy. 2013;33(2):137-143. doi: 10.1002/phar.1186.
27. Valerio M, Muñoz P, Rodríguez-González C, et al. Training should be the first step toward an antifungal stewardship program. Enferm Infecc Microbiol Clin. 2015;33(4):221-227. doi: 10.1016/j.eimc.2014.04.016.
28. Andes D, Pascual A, Marchetti O. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother. 2009;53(1):24-34. doi: 10.1128/AAC.00705-08.