Combination antifungal treatment in critically ill patients failing first-line therapy for invasive fungal infections

Introduction

Combination antifungal therapy (CAT) appears an appealing option in critically ill patients with invasive fungal infections (IFI), especially in those experiencing failure to primary therapy.

Methods

From November 2003 to April 2005, 18 patients affected by IFI (eight with candidemia due to C. albicans, three due to C. glabrata, two due to C. krusei, and five with pulmonary aspergillosis), who had failed primary antifungal therapy, were treated with caspofungin (CAS) 70 mg on the first day, and 50 mg thereafter, plus low-dose (LD) amphotericin B deoxycholate (dAmB) 0.5 mg/kg/day. All patients had high-risk underlying conditions (five acute myelogenous leukemias, six solid tumors, five prolonged ICU stays, and two major abdominal surgical interventions). Failure to prior therapy was determined by: fever and worsening of clinical conditions, and persistent candidemia, or worsening of the lung CT scan together with increase of Aspergillus galactomannan antigenemia (AGA), after 96 hours from the start of antifungal therapy.

Results

All 18 patients were clinically unstable and critically ill, and 13 out of 18 had been admitted to the ICU at the time of switching therapy; five patients never required admission to ICU. All patients survived. Within 72–96 hours from the beginning of CAT, indeed, the clinical stability and fever clearance, together with a negative blood culture, or negative AGA were observed, and confirmed thereafter. LD dAmB did not require any premedication, but none of the patients suffered from side effects, and nor was treatment discontinuation needed. The mean CAT duration was 26 days, but the mean ICU stay was 9 days, before patient transfer to either medical or surgical wards. None of the patients relapsed within a follow up period of at least 60 days from the end of treatment.

Conclusion

CAT including new drugs, such as CAS, is an appealing option supported by promising data. In our experience, CAT with CAS and LD dAmB appears effective in critically ill patients with IFI failing primary treatment. The experimentally demonstrated synergistic activity of dAmB, even at LD, plus CAS seems to be clinically relevant; due to the safety demonstrated, LD dAmB also allows remarkable cost sparing in comparison with lipid formulations. Moreover, compared with the available clinical data in similar situations, both the time to clinical stability and time to discharge from the ICU appear shortened in patients under CAT. Wider clinical studies in these selected settings are needed to clarify the impact on survival of this salvage treatment schedule.