Low-Dose Cyclophosphamide Improves Survival in a Murine Treatment Model of Sepsis

Abstract

Sepsis is a complex medical condition characterized by a systemic inflammatory response in the setting of infection. We hypothesized that combining antibiotics plus an immunosuppressant would protect against the morbidity and mortality of polymicrobial sepsis in mice better than antibiotics alone. We used a murine cecal ligation and puncture model in which mice were treated either with imipenem plus cyclophosphamide or imipenem alone. Titration to a low cyclophosphamide dose revealed that combination therapy increased survival by 20% compared to imipenem alone (56% v. 36%, p < 0.001). To investigate the mechanism by which combination therapy did this, we reviewed quantitative and qualitative markers of the systemic immune response, end-organ damage, and the local immune response at the site of injury. Cyclophosphamide treatment was not associated with depletion of peripheral leukocytes or differences in pulmonary damage. However, mice that received combination therapy had higher plasma G-CSF levels than those treated with antibiotics alone. Additionally, mice treated with cyclophosphamide had higher levels of bacterial colonization in intestinal Peyer’s patch lymph nodes at 72 hours after the septic insult. Intraperitoneal macrophage phenotypes and phagocytosis activity did not differ between groups. We conclude that the inflammatory response plays a significant role in the mortality of polymicrobial sepsis and that the regulation of this element is both feasible and beneficial in this disease model.

Late Therapeutic Intervention with Antibiotics and Fluid Resuscitation Allows for a Prolonged Disease Course with High Survival in a Severe Murine Model of Sepsis

“…The CS and CLP models are similar in that they induce severe intra-abdominal infections via exposure to endogenously-derived polymicrobial bacteria. Indeed, many have found that antibiotic administration after CLP significantly improves survival (15, 17, 18, 21), especially in the young (13). When administration of antibiotics was delayed until 12 hours after CLP and given every 12 hours for 5 days, animals with IL-6 levels >14,000 pg/mL at 6 hours were unable to be rescued (14).…”

Modulation of inflammation and disease tolerance by DNA damage response pathways

“…Similar to topoisomerase II inhibitors, such as anthracyclines, a protective effect in several models of infection has also been recently documented for topoisomerase I inhibitors . The DNA‐damaging chemotherapeutic drug, cyclophosphamide, also improves survival in a mouse model of sepsis, when used at low concentrations in combination with a broad‐spectrum antibiotic . At least in the case of topoisomerase II inhibitors (anthracyclines), ATM is critical for the protection, as discussed before.…”

The Influence of Pain and Analgesia in Rodent Models of Sepsis

“…53 In addition, local lidocaine or bupivacaine has been used at the incision site in surgical models of sepsis either alone or in conjunction with systemic analgesics. 9,43,89 Studies evaluating analgesic efficacy in sepsis have used variable drugs, dosages, and durations of administration (Figure 2). Generally, 2 d of routine analgesia followed by as needed administration are required for rodent laparotomy at this institution.…”