No Signs of New Toxicity When Amphotericin B Lipid Complex (ABLC, ABELCET) and Caspofungin Are Used in Combination in the Treatment of FUO.
Authors: Martino Rodrigo , DuPont Bertrand , Huckle Helen , Chopra Raj 
Published: April 2020

BACKGROUND: Systemic fungal infections including invasive candidiasis and aspergillosis are a significant cause of mortality and morbidity in immunocompromised patients. ABLC is used for the treatment of fungal infections in patients who are intolerant or unresponsive to conventional amphotericin therapy. Caspofungin is a second-line treatment for invasive aspergillosis. The different mechanisms of action of these agents support a dual-therapy regimen; synergistic results have been observed in vitro (Arikan et al, Antimicrob Agents Chemother, 2002;46:245–47). The aim of this open-label, multi-centre study was to investigate safety, tolerability (primary endpoints) and efficacy of concomitant ABLC and caspofungin in immunocompromised patients with refractory FUO (fever of unknown origin).

METHODS: At baseline patients were required to have serum creatinine≤220 μm/L, neutrophil count &lt;0.5x109/L, and at least 72 hours of fever refractory to antibiotics or a recurrence of fever despite continuing antibiotics. Patients received an initial 70 mg caspofungin IV over one hour, followed by ABLC 5 mg/kg IV over 4 hours, then caspofungin 50 mg/day and ABLC 5mg/kg/day. Medication continued until apyrexia or the patient was withdrawn from the study. Tolerability was assessed through incidence and severity of adverse events (AE) including study withdrawal due to Aes. There was a 30-day follow-up period.

RESULTS: 27 immunocompromised patients (mean age 48.9, 18 male) entered the study (leukemia without transplant in 68.2% of patients, haematological malignancy with transplant in 27.3% of patients). Extent of exposure was 11.9 days (mean) for ABLC and 12.2 days (mean) for caspofungin.

Safety: 27 patients were assessed for safety. 18.6% of Aes were considered related to study drug. Drug related Aes included hypokalaemia (4.9%), nausea (4.4%), rigours (4.0%), renal failure (3.5%), diarrhoea (3.5%), hypomagnesaemia (3.1%) and oliguria (1.3%). Three patients experienced grade 3 hypokalaemia related to study medication. Two patients experienced study drug related grade 3 renal failure. This is a similar incidence to single agent use of lipid-associated amphotericin B. The two patients who received concomitant ciclosporin did not develop renal toxicity.

Tolerability: 22 patients were assessed (5 were excluded; 1 protocol violator (inclusion criteria), 2 had fewer than 7 doses of drug and 2 died, reasons unrelated to study drug). 20 (90.9%) patients completed the study without grade 4 or unresolved grade 3 AE. No patient experienced grade 4 AE related to the study drug. No patient withdrew from the study due to AE’s.

Efficacy: 20 patients were assessed (2 patients withdrew consent before study completion). All patients achieved a normal median daily temperature after a mean of 4.3 days (range 2–16 days).

CONCLUSIONS: There was no evidence of newly emerging toxicity associated with the combination of ABLC and caspofungin and no evidence of increase in known toxicity. In addition there is evidence that the combination was efficacious, but there is a clear need for additional studies to confirm this finding.