COMBINATION Antifungal THERAPY for Proven and Probable Invasive Fungal INFECTION IN HIGHLY Immunocompromised Patients.

Despite the advent of new antifungal agents, the prognosis of Invasive Fungal Infections (IFIs) in highly immunocompromised patients remains poor. The current Mycoses Study Group Infectious Diseases Society of America Guidelines do not recommend the use of combination antifungal therapy for the routine treatment of IFIs. However, the use of combination therapy has become very prevalent in treating seriously ill immunocompromised patients. The purpose of this study was to collect the clinical experience of 7 Spanish Haematology Departments in antifungal combination therapy. Thus, we retrospectively examined all antifungal combination therapies applied in patients diagnosed with proven or probable IFIs in our centers. The main goal was to determine efficacy, toxicity and mortality among combinations.

We identified 52 patients (26 males and 26 females) who received antifungal combination therapy for more than a week in our institutions between October 2007 and May 2009. The mean age was 40.7 years (range: 2-73). The diagnosis of IFI was established according to the EORTC/MSG criteria. 31 patients were treated for haematological malignancies with high-dose chemotherapy for remission induction and the others 21 were undergone stem cell transplantation -9 HLA-identical sibling, 11 unrelated SCT, 1 autologous; the stem cells source was cord blood in 9 patients and 6 of the 21 receptors received reduced intensity conditioning regimen-. Underlying diseases were: 21 AML, 17 ALL, 7 MDS, 4 NHL, 1 MM, 1 CLL and 1 Biphenotypic Acute Leukemia.

26 patients had a proven IFI -12 Invasive Lung Aspergillosis, 4 Candidemia (2 C. Krusei and 2 C. Tropicalis), 2 generalized Fusarium, 5 Mucormicosis (3 rinocerebral and 2 pulmonar), 1 generalized Scedosporium Apiospermun, 1 cerebral Cryptococcus and 1 generalized Geotrichum Capitatum- and 26 had a probable IFI (all Invasive Aspergillosis). All patients but 4 received antifungal prophylaxis, 9 with fluconazole, 18 with voriconazole, 15 with itraconazole, 2 with liposomal amphotericin B (AmB) and 2 with caspofungin. Antifungal combination therapy was: AmB + caspofungin in 17 patients; voriconazole + caspofungin in 15 patients; voriconazole + AmB in 15 patients; AmB + posaconazole in 4 patients and voriconazole + anidulafungin in 1 patient. Global mortality was 59.6% (31 patients) and mortality due to IFI was 32,6% (17 patients). The combination therapy was well tolerated and no patient had severe toxicity that leads to discontinue the antifungal treatment, although mild renal and liver toxicity were seen. 37 patients (71.1%) showed a favourable response (28 complete and 9 partial) while unfavourable response were seen in 15 patients (28.9%). When we analyzed the results among antifungal combinations, the response rate was: 82.4% in caspofungin + AmB group, 66.76% in voriconazole + caspofungin group and 60% in voriconazole + AmB group. In spite of the best response in caspofungin + AmB group there were no statistically significances compared with voriconazole + caspofungin (p=0,3, chi square test) and voriconazole + AmB ( p=0,16, chi-square test). In 83.6 % of patients response was accompanied with granulocytic recovery.

The prognosis of antifungal monotherapy for IFIs remains poor. In practice, clinicians are increasingly using antifungal combination therapy in highly immunocompromised patients although appropriate clinical trials evaluating this treatment have not been performed. Our findings show that combination therapy is well tolerated and good results are obtained with highly rates response in patients with this therapy. Future studies should be performed comparing antifungal combined therapy versus monotherapy and among different antifungal combinations.

No relevant conflicts of interest to declare.