The Influence of G-CSF Addition to Antibiotic Treatment: DISCUSSION
Sepsis syndrome consists of a collection of clinical manifestations of sepsis with evidence of organ dysfunction. In the early phase of sepsis, the tissues that usually become damaged and develop organ failure are the lungs. Pulmonary disorder may be followed by disorder of the liver and then the kidneys.
New adjunctive methods are being sought in addition to antimicrobial treatment, which is the primary treatment for sepsis, in order to minimize endothelial damage and organ failures. G-CSF has recently been claimed to increase the neutrophil functions and the regeneration of the infected tissues in both animal and human studies. G-CSF may be administered as a prophylactic treatment or after the first symptoms of sepsis appear. In the present study, G-CSF was administered immediately after bacterial inoculation, and its effects were evaluated histopathologically in the lungs of rats with sepsis. Studies with animal models have demonstrated that G-CSF given as prophylactic treatment or at the onset of the infection was superior to administration after the appearance of infection symptoms. When G-CSF is instituted after the onset of symptoms, it may be argued that inflammatory mediators (such as TNF, IL-1 and IL-8) have already exercised their effects and that the related endothelial damage has possibly already developed. Therefore, it may be considered to play a limited role in the treatment of organ dysfunction due to sepsis. buy vardenafil online
Polymorphonuclear leukocytes (PMNL), including neutrophils, play a critical role in the body’s defense against acute bacterial infection. Mature neutrophils respond to microbial invasion in a variety of ways that serve to destroy the infectious agent and avoid further spread of the infection. The increase in circulating neutrophils in response to acute infection is therefore the key to the host’s defenses. G-CSF modulates not only the defense against invading microorganisms but also the inflammatory response during sepsis. G-CSF release reduces bacterial concentration, endotoxins and TNF formation. G-CSF can directly suppress TNF synthesis and induce release of soluble TNF receptors. These events may eventually help to reduce endothelial damage and prevent potential organ damage or to hasten recovery of the damage that has occurred. The increase in the number of granulocytes after G-CSF treatment is explained not only by increased production but also by suppression of apoptosis. Apopto-sis of lymphocytes and granulocytes is an early event of injury during sepsis and plays a detrimental role in the development of septic shock. In our study, the groups (SAG, SG) receiving G-CSF leukocytes and AN in blood counts demonstrated a statistically significant increase for 36 hours following infection, followed by a tendency to decrease subsequently. This increase is probably caused by both response to infection and the effect of G-CSF release of PMNL from the bone marrow and marginal pool. The tendency to decrease from the 36th hour onwards in the SAG group can be attributed to positive treatment response by limiting the infection. In the group receiving only antibiotics, leukocyte and AN counts increased slowly, reaching a peak level at the 60th hour and all the rats survived, as in the SAG group. While none of the rats with sepsis that were given no treatment survived past the 60th hour, 80% of the rats in the G-CSF-alone group died by the 60th hour. Since G-CSF alone is not capable of controlling infection, only two rats in this group with leukocyte and neutrophil counts close to normal limits survived beyond the 60th hour. The prolongation of survival and close to normal leukocyte and neutrophil counts were probably due to the effects of G-CSF.
Histological examination of the lungs under microscopy revealed that concomitant use of G-CSF with protects the pulmonary architecture with better results (close to those of the control group) for hemorrhage and inflammatory cell infiltration compared with the group receiving canadian antibiotics alone. Similarly, the pulmonary tissues of the rats given G-CSF alone showed less hemorrhage and better preservation of pulmonary architecture in comparison with the rats with sepsis that received no treatment.
Although the survival rate of 20% in the G-CSF-alone group was not significant, G-CSF was considered to assist the tendency towards improvement in the pulmonary tissues of the rats and to exhibit favorable effects on mortality via inhibition of immune suppression by sepsis. The survival rates for rats with severe sepsis may be modulated by reducing the concentration of endothelin-1 in the early phase (four hours), as reported by Lundblad, and early suppression of endothelin inducers, such as endotoxin and TNF by G-CSF, may therefore be the factor responsible for the prolongation of survival. Lundblad et al. also demonstrated in their study that concomitant use of G-CSF and antibiotics (azithromycin is in a group of drugs called macrolide antibiotics) has a synergistic effect on improving resistance against infections by modulating endotoxin and cytokine release and increasing phagocytic ability. Modulation of the inflammatory response during sepsis, thus improving defense against invasion by micro-organisms, reduces the mortality rate in experimental models of sepsis. Positive effects of G-CSF on survival in various animal models have also been reported by other authors. Oz et al. maintain that teicoplanin and G-CSF combination therapy seems effective in reducing mortality rates in pneumonia in an experimental setting. Toda et al. used a rat cecal ligation and puncture (CLP) model and determined a significant improvement in the 48-hour survival rate with a single intraperitoneal administration of 15- or 75 mg of rhG-CSF three hours after the induction of CLP compared with the control CLP group. In a rodent model of E. coli peritonitis, Dunne et al. found that pretreatment with G-CSF reduced mortality. Villa et al., using a CLP model in mice, showed that treatment with G-CSF improved survival when administered before CLP and then followed by antibiotics (Cephalexin canadian is a cephalosporin antibiotic used to treat bacterial infections). In addition, Bauhofer et al. maintain that G-CSF leads to early improvement in sickness behavior in septic rats and suggest that the use of G-CSF may be helpful in the clinical outcome. In contrast to our findings, Saba et al. reported that G-CSF administered either alone or in combination with antibiotics (is an antibiotic in a group of drugs called fluoroquinolones) did not have any effect on survival rates This discrepancy may be attributed to the relatively late onset of treatment at the third hour, after cytokine release—particularly TNF. The diversity of the methods and microorganisms used in various studies may also be an underlying factor responsible for the discrepancies among the mortality results.
G-CSF treatment prevents the circulating neutrophils from diminishing and accelerates neutrophil production in rats with sepsis. G-CSF also leads to increasing phagocytic activity by neutrophils both in tissue and the bloodstream. Several other studies support our results, reporting beneficial effects of G-CSF in septic animals. The effect of antibiotics used in the traditional treatment of sepsis is certainly unquestionable. However, we believe that the addition of new agents, such as G-CSF, particularly in the early phase of infection, to antibiotic treatment would be appropriate for maximizing the effect of antibiotics (Augmentin tablet is a penicillin antibiotic used to treat bacterial infections) as soon as possible and for minimizing the damage caused by inflammation. Based on these findings, it is concluded that adjunctive use of G-CSF with antibiotic treatment (is an antibiotic that treats different types of bacterial infections) would shorten the recovery time for organ failure and reduce sepsis-related fever, infections, the amount and duration of antibiotic (Augmentin medication this medicine is a fluoroquinolone antibiotic used to treat bacterial infections) use, and would thus have a favorable effect on morbidity and cost-effectiveness.