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 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 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?