American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists
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The stability of irinotecan after reconstitution in several vehicles for i.v. infusion was studied. Irinotecan hydrochloride injection was diluted in phosphate buffer solution (pH 4.0, 6.0, and 7.4), 5% dextrose injection, and 0.9% sodium chloride injection to a final concentration of 20 micrograms/mL. The solutions were stored at 25, 37, and 50 degrees C and assayed at intervals up to 24 hours by high-performance liquid chromatography for the concentration of the lactone form of irinotecan remaining. ⋯ The hydrolysis of irinotecan to its carboxylate form was reversible. The rate and extent of hydrolysis increased with increasing pH. The use of a weakly acidic vehicle, such as 5% dextrose injection, for reconstitution of irinotecan may maintain the drug's stability prior to administration.
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The selection of appropriate antimicrobial therapy for patients with sepsis is discussed. Antimicrobial selection is based on the most likely source of infection, the most common pathogens at that site, knowledge of antimicrobial susceptibility patterns in the local community and institution, and host factors. Prompt initiation of appropriate antimicrobial therapy is essential for achieving the best possible outcomes. ⋯ An antipseudomonal beta-lactam with or without an aminoglycoside is recommended for initial therapy in most patients. The role of monotherapy versus combination therapy is controversial. Routine use of vancomycin and antifungal therapy as part of initial regimens should be discouraged but may be justified in specific circumstances.
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Key elements of the current approach to treating sepsis are reviewed, and examples are given to illustrate the difficulty of designing and evaluating trials in sepsis. A patient with sepsis is likely to have symptoms characteristic of the systemic inflammatory response syndrome. Initially, ruling out noninfective causes, locating the site of infection, and obtaining cultures before beginning antimicrobial therapy are critical. ⋯ Recent small studies have shown benefits with low-dose hydrocortisone in patients with refractory sepsis. One challenge in study design is that a therapy may target a subset of patients that cannot be identified at the outset. Management of patients with suspected or documented sepsis focuses on hemodynamic support, appropriate antimicrobial therapy, and other supportive care.
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Clinical trial results for drotrecogin alfa (activated) are discussed in terms of potential effect on morbidity and total cost of care. Interdisciplinary collaboration is crucial for improving care in health systems; teamwork has been shown to improve outcomes in intensive care and reduce costs. The treatment of sepsis is costly and resource intensive. ⋯ No difference was found in total resource use over 28 days between patients who received the drug and those who received placebo, even though more patients who received drotrecogin alfa (activated) survived and thus required treatment. Estimated costs per life-year saved fall within the cost-effective range. When drotrecogin alfa (activated) becomes available for clinical use, pharmacists must systematically assess this new therapeutic tool in terms of health value.
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The role of activated protein C (APC) in coagulation, inflammation, and fibrinolysis and the pharmacology, pharmacokinetics, and trials of recombinant human activated protein C (rhAPC), or drotrecogin alfa (activated), in sepsis are described. Protein C, a naturally occurring vitamin K-dependent serine protease in the blood, remains inactive until exposed to the thrombin-thrombomodulin complex. This change between the inactive and active forms occurs constantly in humans and serves to balance the coagulation cascade. ⋯ These observations led to a Phase III safety and efficacy trial of drotrecogin alfa (activated) that demonstrated a significant improvement in mortality compared with placebo (24.7% versus 30.8%). This 6.1% absolute difference in mortality translates to a 19.4% reduction in relative risk of death in the treated patients. The proper use of drotrecogin alfa (activated) will require careful consideration of appropriate patients to treat and further studies in patient populations that were excluded from the Phase III trial, as well as possible modification of dosing schemes on the basis of patient response.