Pharmacy & Therapeutics - April 2008 - (Page 224) Clinical Focus: Skin Infections and Hemostasis vancomycin, median $256). However, it was the total cost of hospitalization, with a median of $5,027 (range, $4,225– $17,090) for daptomycin and a median of $7,552 for vancomycin (range, $4,386–$19,944) (P < 0.01) that moved the balance in favor of daptomycin. The authors concluded that daptomycin could speed the time to resolution of cSSSIs and could bring about significant reductions in the duration of IV therapy and in associated costs of hospital care. Dr. Rybak put daptomycin’s higher acquisition cost in perspective: We often only think of the acquisition cost of antimicrobials, but the overall cost of patient therapy should also be considered. Drug acquisition cost is actually only a small percentage of the overall treatment cost of a hospital stay for infection. He also voiced concern over growing antimicrobial resistance to vancomycin: Resistance to any antimicrobial is a possibility as long as the antimicrobial is in use. We tend to see changes in susceptibility to antimicrobials over time, especially when we rely on only a few antimicrobials for a particular pathogen, as we have with vancomycin for many years; in fact, we are now approaching the 50year mark in 2008. We’ve had a good run with vancomycin for many years, but we are losing susceptibility. We have several new agents, daptomycin being one that we should use so that we don’t have to rely solely on vancomycin. Recombinant Human Thrombin Less Immunogenic Than Bovine-Derived Thrombin During Surgery The FDA’s approval of a topical recombinant human thrombin of rDNA origin in January 2008 was based on a pivotal clinical trial showing that rThrombin (Recothrom, ZymoGenetics) was as efficacious as, but less immunogenic (antigenic) than, bovine-derived thrombin (bThrombin) for control of hemostasis during surgery. The lead investigator for the phase 3 trial, William C. Chapman, MD, Professor of Surgery at Washington University in St. Louis, Missouri, pointed out that excessive blood loss in surger y, physical trauma, or burn injuries might not be attributable to larger or smaller vessels (and therefore is not addressable by suture ligation or electrocautery) but might result from diffuse bleeding from raw surfaces. In such cases, enhanced hemostatic control can be achieved through the use of topical agents that are designed to increase concentrations of thrombin at the site of injury. Topically applied hemostatic agents derived from plasma have been used for more than 30 years. One current standalone bovine plasma product (Thrombin-JMI, King Pharmaceuticals) is available in the U.S., as are several human plasmaderived thrombins as components of fibrin sealants (e.g., Baxter’s Tisseel and Haemacure’s Hemaseel). Safety concerns with bThrombin have arisen out of reports of antibody development and reports of antibody cross-reaction to homologous human proteins that have led to significant bleeding disorders. About 20% of patients treated with various bThrombin preparations developed antibodies against bovine coagulation factors (e.g., thrombin and factor V). The use of thrombin derived from human plasma also entails the potential risk of transmission of blood-borne pathogens. Dr. Chapman said that in a phase 2 study of rThrombin, which contains no human plasma components, researchers observed no increases in antibody development, compared with a placebo control. A phase 3 trial included patients who were undergoing liver resection, peripheral arterial bypass, and spinal and dialysis access surgery.2 The objective of this randomized, doubleblind trial was to compare the efficacy, safety, and antigenicity of rThrombin and bThrombin as adjuncts to hemostasis. The trial was conducted at 34 medical centers in the U.S. The primary efficacy endpoint was the time to hemostasis; secondary endpoints included the incidence and severity of adverse events, laboratory abnormalities, and development of antibodies to the products studied. In this blinded study, bThrombin 1,000 units/mL or rThrombin 1,000 U/mL was applied to bleeding sites in combination with an absorbable gelatin sponge; 411 patients received the study drug, and 401 patients completed the study (203 receiving bThrombin, and 198 receiving rThrombin). The patients’ median age was approximately 60 years, and 47.5% were women. Surgeries were spinal in approximately 30% of patients, hepatic in about 30%, peripheral arterial bypass in 20%, and arteriovenous graft in about 20%. Hemostasis was achieved within 10 minutes for 95% of patients in each treatment group. Among the 5% not achieving hemostasis within 10 minutes, additional treatment (i.e., usually consisting of more of the study drug) enabled hemostasis in about 85% of cases. Overall complications, including the mortality rate from surgery, adverse events, and laboratory abnormalities, were also similar between both groups. However, differences in antibody development (i.e., seroconversion or more than a unit change of 1 titer) were significant; 43 bThrombin patients (21.5%) developed antibodies, compared with three rThrombin patients (1.5%) (P < 0.0001). None of the three patients in the rThrombin group had abnormal coagulation laboratory results, bleeding, thromboembolism, or hypersensitivity. Patients who developed anti-bThrombin antibodies had an increased incidence of bleeding and thromboembolic events, hypersensitivity, and abnormal activated partial thromboplastin time (aPTT), compared with patients in the bThrombin group without antibodies in a post hoc analysis. Among the three patients in the rThrombin group who tested positive for antibodies, no coagulation, bleeding, thromboembolism, or hypersensitivity was reported. Nearly all patients (205 of 206 receiving bThrombin and 204 of 205 receiving rThrombin) experienced at least one adverse event in the 30-day follow-up period. Events in both groups occurred at a similar rate, with maximum severity usually moderate (56% with bThrombin, 52% with rThrombin). Complications at the incision site were the most common events in 63% of the bThrombin group and in 63% of the rThrombin group. Treatment-related events were rare and affected 1% of bThrombin patients and 3% of rThrombin patients. Two bThrombin patients and one rThrombin patient died, but no deaths were attributed to the study drug. continued on page 249 224 P&T® • April 2008 • Vol. 33 No. 4
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