Case of the Month

January 2018

Adrian Brink

Ampath National Laboratory Services, Milpark hospital, Johannesburg and Division of Infectious Diseases & HIV Medicine, Department of Medicine, University of Cape Town, Cape Town


At a joint infection prevention & control and stewardship meeting, the group discusses the high prevalence of fluconazole-resistant Candida species causing bloodstream infections at a large hospital. In addition, the pharmacy manager presents the escalating cost of antifungal (AF) consumption relative to antibiotics at the hospital. The clinical microbiologist provides data which indicates inconsistent utilization of blood cultures and inappropriate use of fungal biomarker laboratory assays. To address the emerging problems, a decision is made to initiate an antifungal stewardship (AFS) programme (AFSP) in a 25-bed trauma intensive-care unit (TICU) as a pilot to guide hospital-wide implementation later on.

Question 1: What is the first step in implementing an AFS programme?

Answer to Q1

A multidisciplinary team involving the necessary expertise should develop, implement and monitor antifungal stewardship interventions.

To address the complexity of patients at-risk for invasive candidiasis (IC), overcome diagnostic and treatment challenges, and to ensure optimal management of IC, specialist knowledge and experience from a range of healthcare backgrounds (pharmacy, clinical microbiology, infectious diseases, internal medicine, surgery and critical care) is required. Putting together a multidisciplinary team with the necessary expertise is a pivotal and core international recommendation for an AFSP (1, 2). Given the lack of infectious diseases resources in most SA hospitals, utilising existing human resources (i.e. from different specialities including nurses and infection prevention and control practitioners) in a collaborative manner, may enable AFSPs to be embedded in routine practice to ensure sustainability.

Question 2: The chairman of the stewardship and infection control committee presents the resolution and proposed AFSP to the hospital and nursing services manager, who unconditionally supports the intervention, and under guidance constructs a multi-disciplinary team. Management also allocates travel allowance for a clinical microbiologist or infectious disease specialist to assist the team.

Which AFS strategies are possible and may be considered by the hospital team?

Answer to Q2

Depending on resources, a combination of various restrictive, structural and persuasive AFS strategies may be considered (3)

  • Restrictive
    • formulary restriction
    • prior authorization
    • therapeutic substitutions
    • automatic stop orders
  • Structural
    • changing from paper to computerized records
    • rapid laboratory testing
    • therapeutic drug-monitoring
    • computerized decision support systems
    • introduction of quality monitoring mechanisms
  • Persuasive
    • formulating local consensus recommendations
    • distribution of educational materials
    • meetings, ward rounds and outreach visits
    • reminders provided verbally, on paper or on computer
    • prospective audit, intervention and feedback

Prospective audit, intervention and feedback has been shown to be a very effective and safe antibiotic stewardship strategy in SA hospitals, particularly in settings without ID specialists and as such represents a core approach to AFS in accordance with recommendations from international organizations and societies (1). Prospective audit and feedback is a method that allows the AFSP to interact directly with prescribers in order to tailor specific therapy for each patient, depending on the focus of the programme. This strategy is employed after the initial prescribing and dispensing of the antibiotic or antifungal agent.

Question 3: The hospital does not have expertise to authorize use of antifungals prior to prescription/ administration. The team therefore decides to select persuasive strategies by formulating an institutional AFS guideline, widely distributing the latter in addition to other educational material and they choose prospective audit, intervention and feedback as a core strategy.

Which AFS process measures may be considered within the prospective audit, intervention and feedback strategy?

Answer to Q3

Defining process and outcome measures are key in understanding and interpreting quality improvement and stewardship projects and are pivotal for standardized measurement. In this case of an ASFP in a TICU, the process is: how do prescribers diagnose and manage IC in trauma patients? And how do they use the antifungal agents?

Outcome measures relate to impact of the process, i.e. results. Does the process make a difference to the results? What are the results? These could include a shortened stay in ICU or other benefits. Conversely, what are the unfavourable consequences? Is it safe? Process indicators are easier to measure but outcome is more important.

Multi-component AFS process measures for a clinician and/or pharmacist and/or ICU nurse audit that might be considered include:

  • Diagnostic stewardship (use of risk factors, clinical prediction rules and scores, blood cultures, laboratory biomarker assays)
  • “Early” or initial empirical antifungal agent choice, dose including loading doses (according to institutional guideline)
  • Time from prescription of an antifungal agent to administration (“hang-time”)
  • Post-prescription review at 48-72 hours, e.g. de-escalation if the fungal pathogen is susceptible
  • Source control (e.g. central venous catheter [CVC] removal)
  • IV to oral switch
  • Duration of therapy for sepsis

Question 4 The team decides to start auditing in a step-wise manner and to commence with diagnostic stewardship and once use of blood cultures, laboratory biomarkers and clinical prediction scores have improved, to then audit the choices, doses (incl loading doses where applicable) and duration of treatment according to the new institutional Candida guideline. Auditing “hang-time” of antifungals, post-prescription review and CVC removal would follow, once the team, clinicians and ICU nurses were familiar and comfortable with the AFSP.

What AFS outcome measures may be considered for prospective audit and feedback?

Answer to Q4

Multi-component AFS outcome measures that might be considered include:

  • Duration of stay (LOS) (i.e. duration of ICU admission, candidaemia-related stay, etc.)
  • Mortality (30-day crude mortality, candidaemia-related mortality, etc.)
  • Longitudinal impact on cultured isolates from the unit or facility (e.g. Candida antifungal susceptibility pattern, Candida species distribution, prevalence of triazole-resistant Candida species causing blood-stream infections)
  • AF consumption (overall AF consumption, echinocandins, triazoles, amphotericin B)
  • Health economics (AF acquisition costs, cost of IC episode, etc.)

Question 5: The team decides to evaluate the outcome and impact of the AFSP by collecting ICU LOS whilst the pharmacy manager monitors AF consumption using defined daily doses (DDDs) for each of the AF agents available at the hospital. The microbiologist commits to monitor the species distribution and resistance of bloodstream isolates of Candida but will only provide comparative data after 12 months. It was decided not to measure crude mortality at this stage as the intensivists suggest that there are many confounding factors and that more resources are required to make this outcome indicator meaningful. However, to ensure that the AFS initiative doesn’t impact on mortality and is safe to implement throughout the hospital, determining impact on mortality indicators is a priority and management is requested to assist. One member of the team, the infection prevention and control practitioner suggests (after presenting a recent publication) that once all the chosen process measures are audited, that they preferably be audited as a “bundle”.

What constitutes an AFS “bundle”?

Answer to Q5

Targeted antifungal process measures should be audited as an antifungal stewardship bundle that, when implemented together, may result in significantly better outcomes than when implemented individually.

AF process measures should preferably be audited as an AFS bundle which is defined as a small set of evidence-based interventions for a defined patient population and care setting. In contrast to check lists, compliance with bundle components is measured using an all-or-nothing measurement, with a goal of 95% or greater (4).

As mentioned, the first step in the development and implementation of AFS is to build a multidisciplinary team. Using AFS bundles and an all-or-none measurement may change the way care is provided for at-risk patients in important ways including the fact that bundles not only facilitate, but promote awareness that the entire care team must work together in a system designed for reliability (“working as a team in new ways”).

The beneficial impact of ‘bundles’ on clinical outcomes in patients with IC was confirmed for the 1st time recently (5). The composite compliance rate to 9 measures (all-or-nothing) was only 6.9% in this national Japanese study but there was a significant difference in clinical success between patients with and without compliance [92.9% versus 75.8% (p=0.011)]. When step-down oral therapy was excluded from the measures, compliance with the bundles was shown to be an independent predictor of clinical success (OR, 4.42; 95% CI, 2.05–9.52) and mortality (OR, 0.27; 95% CI, 0.13–0.57).

Question 6: A visiting foreign TICU professor visits the hospital as a guest and mentions, at a morbidity and mortality meeting, recent advances in the combined use of clinical risk factors for invasive fungal disease and lab biomarkers with regards to “early-start-stop” therapy. The clinical microbiologist decides to review the relevant publications.

Could clinical prediction rules and scores used concurrently with laboratory biomarker tests possibly assist in identifying ICU patients for an “early start-stop” antifungal therapy approach?

Answer to Q6

The interdependence of risk factors, clinical symptoms/ signs, and biomarkers may assist in the stratification of patients and enable better identification of those candidates for ‘‘early’’ antifungal treatment, as well as those where therapy can be discontinued Identifying patients at-risk for IC includes recognition of a combination of risk factors such as multiple organ failure, sepsis of unknown origin, multisite colonization with Candida spp, mechanical ventilation for >7 days, receipt of broad-spectrum antibiotics and prior surgery, etc. Predictive scores such as the Candida Score (CS) (6) could assist with distinguishing between Candida colonisation versus IC, and probably represents the easiest clinical predictive tool for clinicians, pharmacists and/or ICU nurses in collaborative, multi-disciplinary AFS teams in SA. Such rules permit the stratification and selection of IC high-risk patients who may benefit from early AF therapy. However, from an AFS point of view, given the very low positive predictive values, many AF treatments have been shown to be unnecessary (7). In contrast, the predictive scores have far better negative predictive values (NPV) (8).

Several studies using non-culture-based assays, particularly serum beta-D-glucan (BDG) with a Candida score, have aided in establishing whether an “early” therapeutic start-stop approach (i.e. initiation of AF therapy in at-risk patients followed by close follow-up and discontinuation of AF therapy when IC is excluded), has an impact on the outcomes of ICU patients (9, 10, 11):

  • Combining BDG and the Candida score improves the sensitivity and NPV compared with BDG or the score alone
  • Similar outcomes were observed in a biomarker-based strategy using an algorithm involving BDG, mannan and anti-mannan assays (12)
  • The combined performance of BDG and procalcitonin (PCT) for the differential diagnosis between IC and bacteraemia has also been assessed (13)
  • When both markers indicated IC, they had a higher positive predictive value (PPV) compared to BDG or PCT alone, respectively.
  • When both markers indicated bacteraemia, the NPV for IC was similar to that of BDG used alone.
  • The combined use of PCT and BDG could therefore be helpful in the diagnostic workflow for critically ill patients with suspected candidaemia.

These data suggest that the concurrent use of the Candida and serum BDG and other biomarkers may improve diagnostic stewardship in ICU patients at risk for Candida sepsis, but additional investigations are needed and their use as AFS tools remains to be confirmed. In addition, the negative serum BDG cut-off < 80 pg/ml for C. auris and other Candida species in SA needs to be confirmed.

Question 7: At a follow-up meeting, the team is asked by the pharmacist, to define the indications for prophylaxis which was not specified in detail in the initial hospital guidelines. She states that many patients in the TICU are receiving AFs not prescribed as (“early”) empiric treatment.

What are the evidence-based indications for prophylaxis of invasive candidiasis in adult and neonatal ICU patients?

Answer to Q7

There are very few evidence-based indications for prophylaxis of invasive candidiasis.

AF prophylaxis in non-neutropenic critically ill patients remains controversial. Whilst fluconazole prophylaxis in ICU patients (adults and neonates) may reduce the incidence of IC, collateral damage with regards to epidemiological changes and emergence of resistance in Candida species other than Candida albicans, prohibit universal prophylaxis in this high-risk population.

The approach to prophylaxis should therefore not be universal but rather selective targeting:

  • Surgical patients (14)
    • Presenting with anastomotic leakage after abdominal surgery
    • Re-operation of the digestive tract during the same hospitalization
  • Neonates (15)
    • Extremely low birth weight (ELBW) infants (BW <1000 g) in neonatal ICUs with a baseline rate of IC of 5-10%

Question 8: The pharmacy manager presents the first report of antifungal consumption for the TICU. Several team members comment on the disproportionate amount of voriconazole used in the unit which is deemed inappropriate given the high prevalence of azole-resistant C. parapsilosis and C. auris.

What are the antifungal agents of choice for prophylaxis and treatment of invasive candidiasis in non-neutropenic ICU patients?

Answer to Q8

The unique epidemiology of IC in SA, underscored by the predominance of C. albicans and C. parapsilosis, in the public and private sector, respectively, (16) necessitates multi-disciplinary AFS teams to choose agents for prophylaxis and treatment based on local surveillance data. In this regard, fluconazole resistance and cross resistance to voriconazole in C. parapsilosis in SA is 63% and 44%, respectively.

  • Depending on local epidemiology, fluconazole or an echinocandin or amphotericin B is recommended.
  • Prolonged hospitalization, invasive devices and both antibiotic and antifungal exposure predispose some patients to acquire multi-drug resistant yeasts such as C. auris (17). Pending availability, an echinocandin or amphotericin B is preferred for hospital-acquired IC.


  1. Richardson MD. An introduction to antifungal stewardship. J Antimicrob Chemother 2016; 71 Suppl 2 ii3
  2. Agrawal S, Barnes R, Bruggemann RJ, et al. The role of the multidisciplinary team in antifungal stewardship. J Antimicrob Chemother 2016 ;71 Suppl 2 ii37–ii42
  3. Davey P, Marwick CA, Scott CL, Charani E, McNeil K, Brown E, Gould IM, Ramsay CR, Michie S. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database of Systematic Reviews 2017, Issue 2. Art. No. CD003543
  4. Resar R, Griffin FA, Haraden C, Nolan TW. Using Care Bundles to Improve Health Care Quality. IHI Innovation Series white paper. Cambridge, Massachusetts Institute for Healthcare Improvement; 2012. Available on www.IHI.org. Last accessed 22 September 2017
  5. Takesue Y, Ueda T, Mikamo H, et al Management bundles for candidaemia the impact of compliance on clinical outcomes. J Antimicrob Chemother 2015; 70 587–593
  6. León C, Ruiz-Santana S, Saavedra P, et al. Usefulness of the “Candida score” for discriminating between Candida colonization and invasive candidiasis in non-neutropenic critically ill patients a prospective multicenter study. Crit Care Med 2009, 37:1624-1633
  7. Ferreira D, Grenouillet F, Blasco G, et al. Outcomes associated with routine systemic antifungal therapy in critically ill patients with Candida colonization. Int Care Med 2015;41:1077-1088.
  8. Leon C, Ostrosky-Zeichner L, Schuster M. What’s new in the clinical and diagnostic management of invasive candidiasis in critically ill patients. Int Care Med 2014; 40:808–819
  9. Posteraro B, De Pascale G, Tumbarello M, G, et al. Early diagnosis of candidemia in intensive care unit patients with sepsis a prospective comparison of (1—>3)-β-D-glucan assay, Candida score, and colonization index. Crit Care 2011; 15: R249
  10. Posteraro B, Tumbarello M, De Pascale G, et al. (1,3)-β-D-Glucan-based antifungal treatment in critically ill adults at high risk of candidaemia: an observational study. J Antimicrob Chemother 2016; 71: 2262–2269
  11. Nucci M, Nouer SA, Esteves P, et al. Discontinuation of empirical antifungal therapy in ICU patients using 1,3-β-D-glucan. J Antimicrob Chemother 2016; 71: 2628–2633
  12. Rouzé A, Loridant S, Poissy et al. Biomarker-based strategy for early discontinuation of empirical antifungal treatment in critically ill patients: a randomized controlled trial. Published on-line Sept 2017. Intensive Care Med 2017. DOI 10.1007/s00134-017-4932-
  13. Giacobbe DR, Mikulska M, Tumbarello M, et al. Combined use of serum (1,3)-β-D-glucan and procalcitonin for the early differential diagnosis between candidaemia and bacteraemia in intensive care units. Critical Care 2017; 21:176
  14. Bassetti M, Leon C, Timsit JF. Are prophylactic antifungals in highly colonized patients safe and effective? Intensive Care Med 2015; 41:1336–1339
  15. Healy CM, Baker CJ. Fluconazole prophylaxis in the neonatal intensive care unit. Pediatr Infect Dis J 2009; 28:49
  16. Govender NP, Patel J, Magobo RE, et al. Emergence of azole-resistant Candida parapsilosis causing bloodstream infection: results from laboratory-based sentinel surveillance in South Africa. J Antimicrob Chemother 2016;71(7):1994-2004
  17. Van Schalkwyk E, Shuping L, Ismail H, et al. Independent risk factors associated with Candida auris candidaemia in South Africa – an analysis of national surveillance data, 2016-2017. In abstracts and proceedings. 7th Federation of Infectious Diseases Societies of Southern Africa conference. November 2017

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