Elsevier

Journal of Infection

Volume 80, Issue 3, March 2020, Pages 342-349
Journal of Infection

Efficacy and safety of a comprehensive educational antimicrobial stewardship program focused on antifungal use

https://doi.org/10.1016/j.jinf.2020.01.002Get rights and content

Highlights

  • The PRIOAM improved antifungal use in patients with hospital-acquired candidemia.

  • It resulted in a proportional reduction of antifungal consumption of 38.4%.

  • The most frequently prescribed antifungal agent was fluconazole.

  • The number of Candida spp. with antifungal resistance was remarkably low (4.7%).

  • The reduction in antifungal consumption was safe.

Summary

Objective

Few data exist regarding the impact of antimicrobial stewardship programs on antifungal use. We evaluated the efficacy and safety of a comprehensive long-term antimicrobial stewardship program (ASP) focused on antifungal use.

Methods

During a 9-year period, we quarterly assessed antifungal consumption, incidence density of hospital-acquired candidemia, Candida spp. distribution, antifungal resistance, and crude death rate per 1000 occupied bed days (OBDs) of hospital-acquired candidemia. We performed segmented regression analysis of interrupted time series.

Results

A significant change in trend was observed for antifungal consumption, with a sustained reduction of -0.87% per quarter (95% confidence interval [CI], −1.36 −0.38, p < 0.001), accounting for a final reduction of −38.4%. The main reduction was produced in fluconazole, with a sustained reduction of −1.37% per quarter (95%CI, −1.96 −0.68, p<0.001). The incidence density of hospital-acquired candidemia decreased, with a change in slope of −5.06% cases per 1000 OBDs per year (95%CI, −8.23 −1.77, p = 0.009). The 14-day crude death rate per 1000 OBDs dropped from 0.044 to 0.017 (−6.36% deaths per 1000 OBDs per year; 95%CI, −13.45 −1.31, p = 0.09).

Conclusions

This ASP has succeeded in optimizing the use of antifungal with a long-lasting reduction without increasing the incidence, neither the mortality, of hospital-acquired candidemia.

Introduction

Invasive candidiasis (IC) is the most prevalent invasive fungal infection in humans, being recognized as a major cause of morbidity and mortality in the healthcare environment, especially among immunocompromised and critically ill patients.1, 2, 3, 4 Recent studies indicate that the epidemiology of IC has changed during last years, and although Candida albicans is still the most frequent causative agent of IC, other non-C. albicans species have emerged as important pathogens associated with antifungal resistance.2 Thus, an increasing rate of patients infected with Candida spp. not fully susceptible to azoles or echinocandins have been described in hospitals and healthcare centres worldwide, being frequently associated with a previous high-use of different antifungal classes.5, 6, 7, 8 The selective pressure of antifungals provides an ideal scenario for the emergence of species that are less drug-susceptible than C. albicans, which will colonize the vacant ecological niche. In addition, antifungals can promote different forms of genomic instability in Candida, which are also linked with the development of antifungal resistance.9 This loss of susceptibility is becoming a growing concern in clinical practice, with critical consequences in therapeutic strategies and serious effects on patient outcome.10

Antimicrobial stewardship programs (ASPs) have been recognized as a potential tool to optimise the use of antimicrobial agents in healthcare centres and hospitals, improving patient outcomes, reducing adverse events and the selection pressure associated with antibiotic use.11 However, scarce articles have been reported regarding the development of antifungal stewardship (AFS) programs. Recently, a systematic review 12 including a total of 14 interventional studies showed that AFS programs had a notable impact on antifungal consumption in hospitals, but from these studies, no impact on mortality or on IFI incidence was observed. The authors also noted that only five studies reported an AFS team composed of all the recommended members, and the main intervention was the formulation of recommendations to change treatment (12 out of 14). Due to the low number of research papers on the topic, with significant differences in the methodology performed between them, it is difficult to obtain reliable conclusions about the impact of these programmes on resistance development, IC incidence or mortality.

In our Hospital, an ASP named Institutional Programme for the Optimization of Antimicrobial Treatment (PRIOAM) began on January 2011. Since its implementation, antibiotic use, in-hospital bacterial resistance and mortality rates associated to hospital-acquired bloodstream infections, including hospital-acquired candidemia and multidrug-resistant (MDR) bacteraemia, have been significantly reduced.13,14 In the present manuscript, the objective was to understand specifically the impact of PRIOAM in antifungal use and its ecological and clinical consequences on hospital-acquired candidemia. We hypothesised that a comprehensive ASP program could also optimise the antifungal use, reducing the overall consumption and improving the prescription profile with a consequent reduction in the incidence of hospital-acquired bloodstream infections produced by Candida spp. without increasing mortality or azole resistance rates.

Section snippets

Study design and patients

We conducted a quasi-experimental before-after study of interrupted time-series. The study period included 36 quarters between January 2009 and December 2017. The PRIOAM was implemented on January 2011, and data were prospectively recorded during a 7-years period. All patients aged ≥18 years with hospital-acquired candidemia were included in this study.

Setting

The programme was performed at the University Hospital Virgen del Rocío (Seville, Spain), a teaching Hospital providing a tertiary-care service

Intervention

From 2011 to 2017, the following interventions were made: (a) development of consensual clinical guidelines (http://guiaprioam.com/) for fungal infections and antifungal treatments in different situations such as: (i) febrile neutropenia after chemotherapy; (ii) pneumonia in patients with cancer; (iii) fungal infections in severe burned patients; (iv) antifungal dosing and drug-interactions; (v) and finally, distribution and susceptibility informs to antifungals among blood stream isolates of

Discussion

This study represents the largest educational ASP focused on antifungal use published to date in our knowledge. The results suggest that the implementation and the long-term maintenance of a comprehensive educational ASP program are associated with a substantial and long-lasting reduction on antifungal consumption, which was found to be safe.

From the PRIOAM implementation, we have reported a significant decrease in overall antifungal consumption, which has been maintained over the years with an

Declaration of Competing Interest

J. M. C. has served as a speaker for Novartis, Astellas, Pfizer, Merck Sharp & Dohme, Janssen, and AstraZeneca. M. V. G-N. report receiving personal fees from Merck Sharp & Dohme Spain. The other authors declare that they have no conflicts of interest to report.

Acknowledgments

We acknowledge the invaluable contribution of all the PRIOAM professionals: physicians, clinical microbiologists, pharmacists, nurses, and other members of the hospital. We thank the hospital manager and medical director, and the Andalusian Health Service of the Regional Ministry of Health of Andalucía (Spain) for supporting the ASP.

PRIOAM team

A. B. G-G., Carlos Ortiz, C. F-M., C. I-D., Cristina Montero, Elisa Cordero, Emilio García-Cabrera, Fernando Docobo, Francisco Jiménez-Parrilla, Francisco Porras, G.M-G, G.P, Ignacio Obando, J. A. L, J. L. P-B, J. M., J. M. C., Javier Aznar, Javier Bautista, Josefina Cano, Julia Praena, M. A., M. A. P-M., M. D. N., M. E. J-M., M. L. G., M. R-P de Pipaón, M. V. G-N., Manolo Conde, María J. Rodríguez-Hernández., Marta Herrero, O. N., R. A-M., R. A-V., Raquel Valencia., W. A. G-V.

Financial support

The program received public funding from the Regional Health Ministry of Andalucía (Grant PI-0361-2010), which did not participate in the development of the program or the analysis of its results.

References (55)

  • B.J. Kullberg et al.

    European expert opinion on the management of invasive candidiasis in adults

    Clin Microbiol Infect

    (2011)
  • A. Ramos et al.

    Antifungal stewardship in a tertiary hospital

    Rev Iberoam Micol

    (2015)
  • G.D. Brown et al.

    Hidden killers: human fungal infections

    Sci Transl Med

    (2012)
  • B.J. Kullberg et al.

    Invasive candidiasis

    N Engl J Med

    (2015)
  • S.S. Magill et al.

    Multistate point-prevalence survey of health care-associated infections

    N Engl J Med

    (2014)
  • M.A. Pfaller et al.

    Geographic variations in species distribution and echinocandin and azole antifungal resistance rates among Candida bloodstream infection isolates: report from the sentry antimicrobial surveillance program (2008 to 2009)

    J Clin Microbiol

    (2011)
  • M.A. Slavin et al.

    Candidaemia in adult cancer patients: risks for fluconazole-resistant isolates and death

    J Antimicrob Chemother

    (2010)
  • A.A. Cleveland et al.

    Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008–2011

    Clin Infect Dis

    (2012)
  • O. Lortholary et al.

    Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: a prospective multicenter study involving 2,441 patients

    Antimicrob Agents Chemother

    (2011)
  • R.S. Shapiro

    Antimicrobial-induced DNA damage and genomic instability in microbial pathogens

    PLoS Pathog

    (2015)
  • T.F. Barlam 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)
  • A.L. Bienvenu et al.

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

    J Antimicrob Chemother

    (2018)
  • J. Molina et al.

    Long-Term impact of an educational antimicrobial stewardship program on hospital-acquired candidemia and multidrug-resistant bloodstream infections: a quasi-experimental study of interrupted time-series analysis

    Clin Infect Dis Off Publ Infect Dis Soc Am

    (2017)
  • F. Tissot et al.

    ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients

    Haematologica

    (2017)
  • P.G. Pappas et al.

    Clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases society of America

    Clin Infect Dis Off Publ Infect Dis Soc Am

    (2016)
  • WHOCollaborating center for drug statistics methodology. DDD definition and general considerations. 2016. Available at:...
  • Cited by (0)

    View full text