Discussed in Oxford 13th of June 2014 – report by Joel Meyer
Ostrosky-Zeichner L et al. MSG-01: A Randomized, Double-Blind, Placebo-Controlled Trial of Caspofungin Prophylaxis Followed by Preemptive Therapy for Invasive Candidiasis in High-Risk Adults in the Critical Care Setting. Clinical Infectious Diseases 2014;58(9):1219–26.
Candida is a mould that is not infrequently isolated from cultures of ICU patients, and in the appropriate clinical context, can be diagnostic of invasive candidal infection. Unfortunately, invasive candidiasis in ICU is associated with significant morbidity and mortality, and as such, strategies to prevent or treat this condition are needed. Many strains of candida including glabrata and krusei are resistant to the azole drugs such as fluconazole, therefore echinocandin drugs such as caspofungin, which inhibits fungal cell wall synthesis, are increasingly used. Delays is antifungal treatment have been found in retrospective studies to be associated with poor outcome. To date, only in specific patient subsets (eg transplant, pancreatitis, neonates) has antifungal prophylaxis been shown to improve outcome.
These investigators set out to test the hypothesis that fungal prophylaxis in general at-risk ICU patients could reduce the incidence of invasive candidiasis. They carried out a multicentre randomised double-blind placebo-controlled trial in ICU patients at high risk of invasive candidiasis. Included patients had to meet all of the following criteria: non-pregnant adult, mechanical ventilation, ICU stay > 48 hours, central venous catheter used, broad spectrum antibiotic given, plus one of TPN/pancreatitis/dialysis/major surgery/steroids/other immunosuppressants. Neutropenic patients were excluded.
A total of 219 patients were enrolled and randomised in 15 ICUs in the US. It is important to note that 33 of these patients were immediately excluded at enrolment as per the protocol because they were found to have invasive candidiasis at baseline, and began caspofungin treatment. The diagnosis of invasive candidiasis was made by either positive cultures (ie: proven), or a positive 1,3 beta D glucan serological test in the context of a sepsis syndrome (ie: probable). The remaining “modified intention to treat” patients amounted to 84 in the placebo group and 102 in the caspofungin group (it’s not entirely clear why there is such a discrepancy in numbers). The headline results are that there was no difference in the primary outcome, which was proven or probable invasive candidiasis (9.8% v 16.7%, p = 0.14). There was also no difference between the groups in terms any secondary outcomes including mortality and length of stay. Safety outcomes were not different between the groups.
Having stated the above results for the modified intention to treat group, the authors go on to repeat the analysis with the 33 initially candidiasis-positive patients re-included. This analysis shows a significantly lower rate of candidiasis in the caspofungin group: 18.8% versus 30.4%, p = 0.04. We should remember that this pre-emptive analysis is based on a serological test not a microbiological one, and that the 33 patients included in this analysis did not end up being randomised and their treatment was not blinded. So it’s probably not an internally valid finding and the specified outcomes and analyses are somewhat confusing. But the authors claim this is a useful pre-specified analysis because it serves as a proof of concept for initiating pre-emptive antifungal therapy using the 1,3 beta D glucan assay.
In terms of wider applicability, the glucan assay is not widely available in UK ICUs, and there are doubts about its usefulness as a diagnostic test. Furthermore the incidence of invasive candidiasis in the patients studied was much higher than in other ICU studies and higher than in UK general ICUs. It’s also a relatively small study number for a multicentre comparative effectiveness trial.
What we can probably take from this paper is that, although it may be an apparently safe antifungal drug in ICU, there is no benefit of caspofungin as a pre-emptive or prophylactic agent for invasive candidiasis in the at-risk general ICU patient. Echinocandins are expensive and, in view of emerging antifungal resistance, should be used only where there is a proven benefit.