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Diagnostic versus empirical

in the intensive care setting than the haematology setting.3,4

Defining different approaches to treatment

Empirical treatment has been used historically particularly in high-risk neutropenic patients.5

Essentially, this

approach involves commencing antifungal therapy in patients with persistent fevers who do not respond to antibacterial agents. There is no accepted definition of pre-emptive, targeted or diagnosis-driven strategies in the management of IFI but the common aim of this approach is to limit the use of antifungal therapy to those patients who have early IFI, thereby reducing toxicity, costs and drug resistance.6

Evidence for diagnostic-driven strategies

A number of retrospective or observational studies have attempted to assess the role of diagnostic-driven or pre-emptive therapy for invasive fungal infections.7–11 The initial study by Maertens et al reported a reduction in antifungal use from 35% to 7% based on assessment using galactomannan testing, chest CT scan and bronchoalveolar lavage. This report included 88 patients and focused on 117 febrile neutropenic episodes. All patients received liposomal amphotericin B and the incidence of probable or proven fungal infection was 24%.7 In a single-centre UK centre, we investigated the feasibility of a diagnostic- driven strategy based on high-resolution CT scanning, which again demonstrated a reduction in the usage of antifungal agents. This study showed a 68% reduction in antifungal usage in patients undergoing allogeneic stem cell transplantation. The incidence of probable and proven fungal infections was 4%. This study was limited by its retrospective nature and the lack of galactomannan testing.8

There are limited randomised studies comparing a diagnostic-driven or pre-emptive approach to treatment with empirical treatment. Cordonnier et al undertook a randomised trial in 293 neutropenic patients. The majority of the patients (67%) had acute myeloid leukaemia and patients undergoing allogeneic stem cell transplant were excluded. The control group included patients who were treated with conventional or liposomal amphotericin-B empirically based on

persistent fevers. The other group of patients were monitored with twice- weekly galactomannan testing and commenced conventional or liposomal amphotericin-B only if one

galactomannan index was ≥1.5 or in the presence of sepsis, sinusitis or pneumonia.

Pre-emptive treatment increased the diagnosis of invasive fungal disease, without increasing mortality, and decreased the costs of antifungal drugs. Empirical treatment may provide better survival rates for patients receiving induction chemotherapy. 12

Morrissey et al recently published a randomised, unblinded study comparing a ‘standard diagnostic approach’ including persistent fever of three to five days, microbiological cultures and high-resolution CT of chest with a pre-emptive approach of galactomannan and nested PCR taken twice weekly in inpatients and once weekly in outpatients. A chest CT was still undertaken in cases of persistent fever even in patients with negative biomarkers. The study included 240 patients of whom 80% had undergone allogeneic transplantation.

transplantation. Patients received antifungal therapy if they had an unexplained fever for more than three days. Some patients with a positive PCR result were randomised to receive antifungal therapy of not, but this part of the study only included 21 patients so few conclusions can be drawn.15 The main limitations of the studies undertaken to date are that there are no double-blind, placebo-controlled trials. Many other methodological issues have become apparent including the impact of prophylactic agents, the difficulty in identifying optimal endpoints and how best to incorporate several biomarkers, conventional and radiological investigations.6

Diagnostic-driven strategies in clinical practice

The importance of reducing costs, toxicity and drug resistance has led many centres to adopt their own pre-emptive or diagnostic-driven strategy. In order to implement this change, a multi- disciplinary approach is required including input from haematologist, pharmacist, nursing staff, microbiologist,

“The main limitations of the studies undertaken to date are that there are no double-blind, placebo-controlled trials“

Patients received a variety of antifungal agents and a variety of prophylactic agents. The primary endpoint of the study was the proportion of patients receiving antifungal therapy in a 26-week period following enrolment. Significantly fewer patients received antifungal therapy in the pre-emptive arm (15% versus 32%; p=0.002); mortalities were similar.13 Hebart et al undertook a randomised comparative study of 403 patients undergoing stem cell transplantation. Patients in the empirical group received antifungal therapy based on persistent fevers and the pre-emptive group were treated if panfungal PCR was positive on one occasion. PCRs were checked twice weekly. More antifungal treatment was given in the PCR group as patients were allowed to receive empirical therapy if they had five days of fever or pneumonia. The rate of probable and proven IFI was not significantly different between the two groups.14

a randomised study in patients undergoing reduced-intensity

radiologist, pulmonologist and infection disease specialist. A multi-disciplinary team (MDT) approach allows for specialist expertise and a co-ordinated approach to design an algorithm for use in clinical practice.16

The MDT should consider the patient group treated in the unit, the investigations that are available, the timescale for receipt of results of investigations and the prevalence of particular fungal pathogens. Other considerations would include the choice of prophylactic and therapeutic agent and the potential for interaction with other commonly used medications. Any strategy that was adopted would subsequently require to be audited to ensure adherence to the protocol and the incidence of probable/proven fungal infections. An alternative approach would be to enrol patients into a suitable clinical trial.

Blennow et al also published

Conclusions In view of the limitations of the studies undertaken to date it is difficult to draw


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