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Influence of adjunctive interferon-gamma on treatment of gentamicin- and vancomycin-resistant Enterococcus faecalis
C O Onyeji1, K Q Bui, D P Nicolau
1Department of Pharmacy Research, Hartford Hospital, CT 06102, USA.
Abstract:
Increasing antibiotic resistance and the development of multidrug-resistance in the enterococci has complicated the treatment of serious enterococcal infections. It has been demonstrated in vitro that interferon-gamma (IFN-gamma) significantly augments the activities of gentamicin and vancomycin against Enterococcus faecalis resistant to these antibiotics. The present study was aimed at determining whether this beneficial effect of IFN-gamma on antienterococcal antibiotic activity can be validated in vivo. Following intraperitoneal inoculation in mice with a gentamicin- and vancomycin-resistant E. faecalis clinical isolate, the animals received IFN-gamma, antibiotic or a combination of both agents, subcutaneously, at determined dosing regimens. Treatment with IFN-gamma alone significantly improved survival of infected animals in a dose-dependent manner. High dose IFN-gamma was not beneficial and the level of enterococcal infectious burden influenced the effectiveness of the cytokine. The addition of IFN-gamma to therapy with gentamicin or vancomycin, or a combination of both antibiotics was associated with a marked increase in survival of infected non-neutropenic mice compared to treatments with the agents alone. However, the same treatments made in infected neutropenic mice did not show an enhancement effect by IFN-gamma after a combination therapy with antibiotics. In a study to examine pharmacokinetic interactions, concurrent administration with IFN-gamma significantly modified the disposition of gentamicin but not that of vancomycin. The results of this study suggest that the use of IFN-gamma in combination with vancomycin or gentamicin is a new treatment option that might improve the outcome of therapy of multidrug-resistant E. faecalis infections.
Insights
Interferon-gamma (IFN-gamma) enhances antibiotic effectiveness against multidrug-resistant Enterococcus faecalis infections in mice. Combining IFN-gamma with gentamicin or vancomycin improved survival, offering a potential new treatment strategy.
Area of Science:
- Infectious Diseases
- Immunology
- Pharmacology
Background:
- Multidrug-resistance in enterococci complicates treatment of serious infections.
- In vitro studies show interferon-gamma (IFN-gamma) potentiates gentamicin and vancomycin activity against resistant Enterococcus faecalis.
Purpose of the Study:
- To validate the in vivo efficacy of IFN-gamma in augmenting antienterococcal antibiotic activity.
- To evaluate IFN-gamma as a potential therapeutic agent for multidrug-resistant Enterococcus faecalis infections.
Main Methods:
- A mouse model was used, infected with a resistant E. faecalis clinical isolate.
- Animals received subcutaneous IFN-gamma, antibiotics (gentamicin/vancomycin), or combination therapy.
- Survival rates, infectious burden, and pharmacokinetic interactions were assessed.
Main Results:
- IFN-gamma alone improved survival dose-dependently; high doses were not beneficial.
- Combination therapy with IFN-gamma and antibiotics significantly increased survival in non-neutropenic mice.
- IFN-gamma altered gentamicin pharmacokinetics but not vancomycin's; no enhancement seen in neutropenic mice.
Conclusions:
- IFN-gamma combined with vancomycin or gentamicin shows promise for treating multidrug-resistant E. faecalis infections.
- This combination represents a potential new therapeutic option for challenging enterococcal infections.
