Interaction between caspofungin or voriconazole and cefoperazone-sulbactam or piperacillin-tazobactam by in vitro and in vivo methods

Immunosuppressive patients are at risk of fungal and bacterial infections. Therefore, these patients receive prophylactic, preemptive, empirical or target antifungal and concomitant antibiotic therapy. To this end, caspofungin (CAS) or voriconazole (VRC) antifungals and cefoperazone-sulbactam (CPZ/SAM) or piperacillin-tazobactam (PIP/TAZ) antibiotics may be used. Here, we aimed to investigate the interaction between these antifungals and antibiotics by in vitro and in vivo methods. The interaction was tested by chequerboard analysis and fractional inhibitory concentration index (FICI). It was also tested in a neutropenic mice-invasive candidiasis model and evaluated by fungal burden in kidney tissue of infected animals from the first day to the fifth day of treatment with 24h intervals. A synergism was detected between CAS and CPZ/SAM (FICI=0.1) and PIP/TAZ (FICI=0.3). Fungal burden in tissues of drug-treated mice was reduced compared with controls in a time-dependent manner. In comparison with CAS-alone treated group, there were 1.32log(10) reductions of fungal burden in CAS+CPZ/SAM (p=0.002) and in CAS+PIP/TAZ group (p=0.14). The same interactions were not found with VRC and antibiotics. CPZ/SAM had stronger synergistic interaction with CAS than PIP/TAZ. The mechanism of synergism is not well understood. This is most likely due to an increase in the anticandidal effect of CAS plus antibiotics.