A Randomized Controlled Trial of Filgrastim as an Adjunct to Antibiotics for Treatment of Hospitalized Patients with Community‐Acquired Pneumonia

Nelson, Steve; Belknap, Steven M.; Carlson, Richard W.; Dale, David C.; deBoisblanc, Ben; Farkas, Stephen A.; Ho, Hoi; Marrie, Thomas J.; Movahhed, H.; Root, Richard K.; Wilson, John W.

doi:10.1086/515694

Cited by 190 publications

(118 citation statements)

References 11 publications

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“…G-CSF has also recently been evaluated as an adjunctive agent for treatment of infection in nonneutropenic patients, but with mixed results. The addition of G-CSF to standard therapy in severe community-acquired pneumonia had no beneficial effect (26), although in diabetic patients with foot infections, administration of G-CSF accelerated resolution of cellulitis, reducing antibiotic use and hospital length of stay (27). Our findings suggest that pretreatment with G-CSF before infection becomes manifest, particularly in patients at risk such as those undergoing surgical procedures, may be an effective adjunct or alternative to antibiotic prophylaxis in preventing bacterial infection.…”

Section: Discussionmentioning

confidence: 93%

Production of Granulocyte Colony-Stimulating Factor in the Nonspecific Acute Phase Response Enhances Host Resistance to Bacterial Infection

Noursadeghi

Bickerstaff

Herbert

et al. 2002

The Journal of Immunology

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Mice mounting an acute phase response, induced by sterile inflammation after a single s.c. injection of casein 24 h beforehand, were remarkably protected against lethal infection with Gram-positive or Gram-negative bacteria. This was associated with enhanced early clearance of bacteremia, greater phagocytosis and oxidative burst responses by neutrophils, and enhanced recruitment of neutrophils into tissues compared with control, nonacute phase mice. Casein-induced inflammation was also associated with increased concentrations of G-CSF in serum, and administration of neutralizing Ab to this cytokine completely abrogated protection against Escherichia coli infection after casein pretreatment. Injection of recombinant murine G-CSF between 3 and 24 h before infection conferred the same protection as casein injection. In contrast, the casein-induced acute phase response affected neither serum values of TNF-α, IL-1β, or IL-6 after E. coli infection nor susceptibility to LPS toxicity. Furthermore, protection against infection was unaffected in IL-1R knockout mice, which have deficient acute phase plasma protein responses, or after nonspecific inhibition of acute phase protein synthesis by d-galactosamine or specific depletion of complement C3 by cobra venom factor. Increased production of G-CSF in the acute phase response is thus a key physiological component of host defense, and pretreatment with G-CSF to prevent bacterial infection in at-risk patients now merits further study, especially in view of increasing bacterial resistance to antibiotics.

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Section: Discussionmentioning

confidence: 93%

Production of Granulocyte Colony-Stimulating Factor in the Nonspecific Acute Phase Response Enhances Host Resistance to Bacterial Infection

Noursadeghi

Bickerstaff

Herbert

et al. 2002

The Journal of Immunology

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“…Treatment of HIVinfected subjects with G-CSF during opportunistic infections may enhance clearance of opportunistic and nonopportunistic organisms. Furthermore, preliminary data suggest that the addition of G-CSF to standard antibiotic therapy may enhance the treatment of community acquired pneumonia in non-HIV patients (40).…”

Section: Discussionmentioning

confidence: 99%

Granulocyte colony-stimulating factor administration to HIV-infected subjects augments reduced leukotriene synthesis and anticryptococcal activity in neutrophils.

Coffey¹,

Phare²,

George³

et al. 1998

J. Clin. Invest.

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Neutrophil (PMN) dysfunction occurs in HIV infection. Leukotrienes (LT) are mediators derived from the 5-lipoxygenase (5-LO) pathway that play a role in host defense and are synthesized by PMN. We investigated the synthesis of LT by PMN from HIV-infected subjects. There was a reduction (4.0 Ϯ 1.3% of control) in LT synthesis in PMN from HIV-infected compared with normal subjects. This was associated with reduced expression of 5-LO-activating protein (31.2 Ϯ 9.6% of normal), but not of 5-LO itself. Since HIV does not directly infect PMN, we considered that these effects were due to reduced release of cytokines, such as granulocyte colony-stimulating factor (G-CSF). We examined the effect of G-CSF treatment (300 g daily for 5 d) on eight HIV-infected subjects. PMN were studied in vitro before therapy (day 1) and on days 4 and 7. LTB 4 synthesis was increased on day 4 of G-CSF treatment, and returned toward day 1 levels on day 7. 5-LO and 5-LO-activating protein expression were increased in parallel. As a functional correlate to this increase in PMN LT synthesis by G-CSF, we examined the effects on killing of Cryptococcus neoformans . Anticryptococcal activity of PMN from HIV-infected subjects was less than that of PMN from normal subjects. G-CSF treatment improved fungistatic activity of PMN. This increase in antifungal activity was attenuated by in vitro treatment with the LT synthesis inhibitor, MK-886. In conclusion, PMN from HIV-infected subjects demonstrate reduced 5-LO metabolism and antifungal activity in vitro, which was reversed by in vivo G-CSF therapy. ( J. Clin. Invest. 1998. 102:663-670.)

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“…G-CSF therapy thereby seems to be efficacious against bacterial infection, because neutrophils play an important role in the acute response of the host to bacterial infections [24]. However, we should be careful to augment neutrophil function in the burn-injured hosts, because it might possibly induce an over production of superoxide anions from the neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Diverse Enhancement of Superoxide Production from Kupffer Cells and Neutrophils after Burn Injury or Septicemia

Masuda

Kinoshita

Ono

et al. 2006

J. Clin. Biochem. Nutr.

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Summary Objective: To investigate the difference in superoxide production from circulating neutrophils and Kupffer cells between in the mice after burn injury and mice suffering from bacterial septicemia.Background: Both severe burn injury and septicemia can result in a critical / fatal outcome for the patients even after initial resuscitation. Analyses of defense mechanisms in the host who survive after severe stress are thereby very important for improvement of intensive care.Method: Either burn injury or inoculations with Peudomonas aeruginosa were subjected to C57BL /6 mice. After 7 days, circulating neutrophils and Kupffer cells were obtained from the mice to examine superoxide or cytokine production.Results: Neither of the mouse groups showed any pathological changes in major organs or any elevations in the serum transaminase or TNF levels at 7 days after burn injury or bacterial inoculation. The burn injured mice showed significantly higher superoxide production from neutrophils by stimulation with phorbor myristate acetate (PMA) or opsonized zymosan (OZ) than that from Kupffer cells. In contrast, the bacterial challenged mice showed a significantly higher superoxide production from Kupffer cells than that from neutrophils. In addition, the burn injured mice showed a significantly higher production of IL-10, namely antiinflammatory cytokine, from the Kupffer cells by LPS stimulation than the bacterial challenged mice while the bacterial challenged mice showed a significantly higher production of IL-12, namely proinflammatory cytokine, from Kupffer cells by LPS stimulation than the burn injured mice.Conclusions: Neutrophils might thus be activated to a greater degree than Kupffer cells in mice after burn injury, while Kupffer cells might be activated more than neutrophils after bacterial septicemia.

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A Randomized Controlled Trial of Filgrastim as an Adjunct to Antibiotics for Treatment of Hospitalized Patients with Community‐Acquired Pneumonia

Cited by 190 publications

References 11 publications

Production of Granulocyte Colony-Stimulating Factor in the Nonspecific Acute Phase Response Enhances Host Resistance to Bacterial Infection

Production of Granulocyte Colony-Stimulating Factor in the Nonspecific Acute Phase Response Enhances Host Resistance to Bacterial Infection

Granulocyte colony-stimulating factor administration to HIV-infected subjects augments reduced leukotriene synthesis and anticryptococcal activity in neutrophils.

Diverse Enhancement of Superoxide Production from Kupffer Cells and Neutrophils after Burn Injury or Septicemia

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