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

Onyeji, Cyprian O.; Bui, Khanh Q.; Nicolau, David P.; Nightingale, Charles H.; Bow, Laurine; Quintiliani, Richard

doi:10.1016/s0924-8579(99)00055-2

Cited by 10 publications

(14 citation statements)

References 41 publications

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“…Neutrophils were found to impact the efficacy of therapeutic interventions (i.e., granulocyte colony-stimulating factor or IFN-␥ given together with appropriate antibiotics) after i.p. infection with E. faecalis (30,31). However, these studies, in which neutropenia was induced by cyclophosphamide, did not directly investigate the role of neutrophils in host defense against E. faecalis peritonitis (30,31).…”

Section: Discussionmentioning

confidence: 99%

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Neutrophils Are Essential for Rapid Clearance ofEnterococcus faeciumin Mice

Leendertse

Willems²,

Giebelen

et al. 2009

Infect Immun

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A progressive increase in infections with multiresistant Enterococcus faecium has been reported, especially in cancer patients and neutropenic patients. Despite its increasing importance as a nosocomial pathogen, knowledge of the pathogenesis of E. faecium infections is highly limited. In this study, we investigated the role of neutrophils during peritonitis with subsequent bacteremia caused by E. faecium. Therefore, we depleted neutrophils by intraperitoneal injections of monoclonal antibody RB6-8C5. Mice were followed for 5 days, and the enterococcal outgrowth and inflammatory response were compared between neutropenic mice and immunoglobulin G-injected control mice. Neutropenic mice demonstrated a severe delay in enterococcal clearance from all cultured organs (peritoneal fluid, blood, and lung and liver tissue). In particular, neutropenic mice remained bacteremic for up to 3 days, whereas all nonneutropenic mice had cleared the bacteria from circulation by 2 days. Furthermore, neutropenic mice displayed elevated peritoneal cytokine and chemokine levels 1 day after the infection and attracted fewer macrophages into the peritoneal cavity. In the circulation, a prolonged elevation of tumor necrosis factor alpha, interleukin-6, and the acute-phase proteins serum amyloid A and complement 3 were measured in neutropenic mice. In conclusion, attraction of neutrophils to the primary site of E. faecium infection is important for a rapid clearance of this bacterium, thereby attenuating a systemic inflammatory response.

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Section: Discussionmentioning

confidence: 99%

“…infection with E. faecalis (30,31). However, these studies, in which neutropenia was induced by cyclophosphamide, did not directly investigate the role of neutrophils in host defense against E. faecalis peritonitis (30,31). To deplete mice of neutrophils, MAb RB6-8C5 was used.…”

Section: Discussionmentioning

confidence: 99%

Neutrophils Are Essential for Rapid Clearance ofEnterococcus faeciumin Mice

Leendertse

Willems²,

Giebelen

et al. 2009

Infect Immun

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“…The combination of IFN-␥ and either vancomycin or gentamicin has been reported to improve therapy against drug-resistant Enterococcus faecalis infection in mice (32,33). Doherty and Sher (8) showed that low doses of IL-12 together with either clarithromycin or rifabutin decreased the splenic loads of M. avium to a greater extent than treatment with the cytokine or drugs alone.…”

Section: Discussionmentioning

confidence: 99%

Intranasal Interleukin-12 Treatment Promotes Antimicrobial Clearance and Survival in PulmonaryFrancisella tularensissubsp.novicidaInfection

Pammit

Budhavarapu

Raulie

et al. 2004

Antimicrob Agents Chemother

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Francisella tularensis is a highly virulent facultative intracellular bacterium and is considered a potential biological warfare agent. Inhalation tularemia can lead to the development of bronchopneumonia, which is frequently fatal without medical intervention. Treatment strategies that directly target the respiratory mucosa may extend the efficacy of therapy, particularly for the medical management of acute aerosol exposure. To this end, we describe an intranasal (i.n.) strategy for the treatment of pulmonary Francisella infection in mice that uses a combinatorial approach with the conventional antibiotic gentamicin and interleukin 12 (IL-12). The i.n. administration of IL-12 alone promoted bacterial clearance and extended the time to death but did not prevent mortality against lethal pulmonary challenge with Francisella tularensis subsp. novicida. However, i.n. treatment with gentamicin and IL-12 therapeutically at 8 and 24 h after challenge markedly enhanced the rate of survival (70 to 100%) against pulmonary infection compared to the rates of survival for animals treated with antibiotic alone (17%) or IL-12 alone (0%). A delay in combinatorial therapy over a span of 4 days progressively decreased the efficacy of this treatment regimen. This combinatorial treatment was shown to be highly dependent upon the induction of endogenous gamma interferon and may also involve the activation of natural killer cells. Together, these findings suggest that IL-12 may be a potent adjunct for chemotherapy to enhance drug effectiveness against pulmonary Francisella infection.

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“…For example, the combination of IFN-␥ with the antibiotics gentamicin and vancomycin enhanced the clearance of Enterococcus faecalis in an in vitro neutrophil infection model (21). However, in a mouse model of E. faecalis infection, only low doses of IFN-␥ increased the effectiveness of antimicrobial therapy, while high IFN-␥ doses were ineffective or deleterious (20). In a Francisella novicida infection model, the intranasal administration of recombinant interleukin-12 (rIL-12; which induced IFN-␥ production) increased the effectiveness of an-timicrobial therapy (22).…”

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confidence: 99%

Immunotherapy Markedly Increases the Effectiveness of Antimicrobial Therapy for Treatment ofBurkholderia pseudomalleiInfection

Propst

Troyer

Kellihan

et al. 2010

Antimicrob Agents Chemother

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Burkholderia pseudomallei is a soil bacterium that is endemic in southeast Asia and northern Australia and that can cause both acutely lethal pneumonia and chronic systemic infections in humans. The effective treatment of infection with B. pseudomallei requires rapid diagnosis and prolonged treatment with high doses of antimicrobials, and even with appropriate antibiotic therapy, patient relapses are common. Thus, new approaches to the treatment of B. pseudomallei infections are needed. In the present study, we asked whether active immunotherapy with gamma interferon (IFN-␥), a key cytokine regulating the intracellular replication of B. pseudomallei, could increase the effectiveness of conventional antimicrobial therapy for B. pseudomallei infection. Macrophage infection assays and in vivo pulmonary challenge models were used to assess the inhibitory effects of combined treatment with IFN-␥ and ceftazidime on B. pseudomallei infection. We found that treatment with even very low doses of IFN-␥ and ceftazidime elicited strong synergistic inhibition of B. pseudomallei growth within infected macrophages. In vivo, active immunotherapy markedly potentiated the effectiveness of low-dose ceftazidime therapy for the treatment of infected mice in a pulmonary challenge model of B. pseudomallei. Combined treatment was associated with a significant reduction in the bacterial burden and a significant lessening of bacterial dissemination. We concluded, therefore, that immunotherapy with either endogenous or exogenous IFN-␥ could significantly increase the effectiveness of conventional antimicrobial therapy for the treatment of acute B. pseudomallei infection.

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

Cited by 10 publications

References 41 publications

Neutrophils Are Essential for Rapid Clearance ofEnterococcus faeciumin Mice

Neutrophils Are Essential for Rapid Clearance ofEnterococcus faeciumin Mice

Intranasal Interleukin-12 Treatment Promotes Antimicrobial Clearance and Survival in PulmonaryFrancisella tularensissubsp.novicidaInfection

Immunotherapy Markedly Increases the Effectiveness of Antimicrobial Therapy for Treatment ofBurkholderia pseudomalleiInfection

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