title: Influence of adjunctive interferon-gamma on treatment of gentamicin- and vancomycin-resistant Enterococcus faecalis infection in mice.
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.
authors.affiliation: Department of Pharmacy Research, Hartford Hospital, CT 06102, USA.
authors.forename: C O
authors.initials: CO
authors.lastname: Onyeji
authors.forename: K Q
authors.initials: KQ
authors.lastname: Bui
authors.forename: D P
authors.initials: DP
authors.lastname: Nicolau
authors.forename: C H
authors.initials: CH
authors.lastname: Nightingale
authors.forename: L
authors.initials: L
authors.lastname: Bow
authors.forename: R
authors.initials: R
authors.lastname: Quintiliani
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D013293:Enterococcus faecalis / Q000187:drug effects* / Q000302:isolation & purification; D005260:Female; D005839:Gentamicins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D007371:Interferon-gamma / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D014640:Vancomycin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D005839:Gentamicins; D014640:Vancomycin; D007371:Interferon-gamma