Influence of adjunctive interferon-gamma on treatment of gentamicin- and vancomycin-resistant Enterococcus faecalis infection in mice

Increasing antibiotic resistance and the development of multidrug-resistanc e in the enterococci has complicated the treatment of serious enterococcal infections. It has been demonstrated in vitro that interferon-gamma (IFN-ga mma) significantly augments the activities of gentamicin and vancomycin aga inst Enterococcus faecalis resistant to these antibiotics. The present stud y was aimed at determining whether this beneficial effect of IFN-gamma on a ntienterococcal antibiotic activity can be validated in vivo. Following int raperitoneal inoculation in mice with a gentamicin- and vancomycin-resistan t E. faecalis clinical isolate, the animals received IFN-gamma, antibiotic or a combination of both agents, subcutaneously, at determined dosing regim ens. Treatment with IFN-gamma alone significantly improved survival of infe cted animals in a dose-dependent manner. High dose IFN-gamma was not benefi cial and the level of enterococcal infectious burden influenced the effecti veness of the cytokine. The addition of IFN-gamma to therapy with gentamici n or vancomycin, or a combination of both antibiotics was associated with a marked increase in survival of infected non-neutropenic mice compared to t reatments with the agents alone. However, the same treatments made in infec ted neutropenic mice did not show an enhancement effect by IFN-gamma after a combination therapy with antibiotics. In a study to examine pharmacokinet ic interactions, concurrent administration with IFN-gamma significantly mod ified the disposition of gentamicin but not that of vancomycin. The results of this study suggest that the use of IFN-gamma in combination with vancom ycin or gentamicin is a new treatment option that might improve the outcome of therapy of multidrug-resistant E. faecalis infections. (C) 1999 Elsevie r Science B.V. and International Society of Chemotherapy. All rights reserv ed.