Modified abbreviated burn severity index as a predictor of in-hospital mortality in patients with inhalation injury: development and validation using independent cohorts.

PURPOSE: The ability to accurately evaluate the severity of inhalation injury can help to optimize patient care. However, there is no accepted severity grading system, especially for inhalation injury. METHODS: We screened a multicenter burn registry and included adult patients who required oxygen treatment or mechanical ventilation. After the patient data were divided into development and validation cohorts, missing values were replaced with multiple imputation. Twelve potential predictors were analyzed using multivariate logistic regression to identify prognostic variables for in-hospital mortality and scores were assigned to each predictor based on odds ratios to develop the Modified Abbreviated Burn Severity Index, mABSI. The mABSI was validated using c-statistics and calibration curves. RESULTS: We randomly assigned 1377 and 919 patients to the development and validation cohorts, respectively. Age, self-inflicted injury, cutaneous burn area, and mechanical ventilation requirement were identified as independent predictors, and the mABSI (1-17 scale) was, thus, developed. The mABSI has a high discriminatory power (c-statistic = 0.94; 95% CI 0.92-0.97), and both estimated and observed in-hospital mortalities increased from 1% at score ≤ 5 to almost 100% at score ≥ 14 with linear calibration plots. CONCLUSIONS: We developed and validated the mABSI which accurately predicts in-hospital mortality.

Efficacy and safety of intravenous daptomycin in Japanese patients with skin and soft tissue infections.

Daptomycin is a lipopeptide antibiotic active against gram-positive organisms and recently approved for marketing in Japan. This study investigates the efficacy and safety of daptomycin in Japanese patients with skin and soft tissue infections (SSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) for regulatory filing in Japan. Overall, 111 Japanese patients with SSTI were randomized in this open-label, randomized, active-comparator controlled, parallel-group, multicenter, phase III study. Patients received intravenous daptomycin 4 mg/kg once daily or vancomycin 1 g twice daily for 7-14 days. Efficacy was determined by a blinded Efficacy Adjudication Committee. Among patients with SSTIs caused by MRSA, 81.8 % (95 % CI, 69.1-90.9) of daptomycin recipients and 84.2 % (95 % CI, 60.4-96.6) of vancomycin recipients achieved a successful clinical response at the test-of-cure (TOC) visit. The microbiological success rate against MRSA at the TOC visit was 56.4 % (95 % CI, 42.3-69.7) with daptomycin and 47.4 % (95 % CI, 24.4-71.1) with vancomycin. Daptomycin was generally well tolerated; most adverse events were of mild to moderate severity. The measurement of daptomycin concentration in plasma revealed that patients with mild or moderate impaired renal function showed similar pharmacokinetics profiles to patients with normal renal function. Clinical and microbiological responses, stratified by baseline MRSA susceptibility, suggested that patients infected with MRSA of higher daptomycin MIC showed a trend of lower clinical success with a P value of 0.052 by Cochran-Armitage test. Daptomycin was clinically and microbiologically effective for the treatment of MRSA-associated SSTIs in Japanese patients.

Pharmacokinetic-pharmacodynamic relationship of arbekacin for treatment of patients infected with methicillin-resistant Staphylococcus aureus.

Arbekacin is widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). In this study, we have determined the optimal concentration targets of arbekacin for both efficacy and safety. A pharmacokinetic-pharmacodynamic analysis was performed to relate exposure to the drug and clinical cure/improvement or nephrotoxicity. Since we have reported the population pharmacokinetic parameters for arbekacin in the preceding paper (Y. Tanigawara, R. Sato, K. Morita, M. Kaku, N. Aikawa, and K. Shimizu, Antimicrob. Agents Chemother. 50:3754-3762, 2006), individual exposure parameters, such as area under the concentration-time curve (AUC), peak concentration (C(max)), AUC/MIC, C(max)/MIC, and trough concentration (C(min)) were estimated by the Bayesian method. Logistic regression was used to describe the relationship between exposure to the drug and the probability of clinical cure/improvement or nephrotoxicity. For the clinical efficacy analysis, 174 patients confirmed to have an MRSA infection were evaluated. The C(max), C(min), and AUC of arbekacin were associated with the probability of clinical cure/improvement during monotherapy. It was shown that the probability of cure/improvement rose when the C(max) of arbekacin was increased, with an odds ratio of 6.7 for a change in C(max) from 7.9 to 12.5 microg/ml (P = 0.037). For the nephrotoxic risk analysis, 333 patients were included, regardless of whether a pathogen was identified. Logistic regression analysis revealed C(min) and AUC as risk factors of nephrotoxicity (P < 0.005). The estimated probabilities of arbekacin-induced nephrotoxicity were 2.5, 5.2, and 13.1% when the C(min) values were 1, 2, and 5 microg/ml, respectively. The present findings are useful for optimizing the individual dose of arbekacin for the treatment of MRSA-infected patients.

Cost-minimisation analysis of sivelestat for acute lung injury associated with systemic inflammatory response syndrome.

OBJECTIVES: To conduct a cost-minimisation analysis of sivelestat sodium hydrate treatment for patients in the intensive care unit (ICU) with acute lung injury (ALI) associated with systemic inflammatory response syndrome (SIRS) caused by infection. DESIGN: The analysis was performed based on data from a phase III randomised, multicentre, double-blind, controlled clinical study of up to 14 days treatment with sivelestat, in which the effect of intravenous sivelestat at a high dose (0.20 mg/kg/h; the sivelestat group) was compared with that at a low dose (0.004 mg/kg/h, effectively a placebo; the control group). PATIENTS: Patients with ALI associated with SIRS caused by infection, who began their treatment under mechanical ventilation management in the ICU. METHODS: A four-stage Markov model was constructed to represent the possible conditions of an ALI patient: ICU plus intubated mechanical ventilation; ICU plus weaned from a mechanical ventilator; admission to the general ward; and death. The base-case analysis used a mechanical ventilator weaning daily rate of 2.9% for the control group and 4.0% for the sivelestat group, and the same mortality (1.2%) for both groups at all stages of the Markov model. Medical costs were estimated from standard fees and Japanese National Health Insurance drug prices included fees for hospitalisation within the ICU and general wards, mechanical ventilation, examinations and drug expenditure. Costs were in 2001 values. Sensitivity analyses were performed by varying the weaning rate, mortality, time between weaning and discharge to the general ward, and drug costs. PERSPECTIVE: Payers of healthcare costs. MAIN OUTCOMES: The expected 30-day medical costs per patient in the control and sivelestat groups were Japanese yen (yen) 4,144,887 and 3,975,451 yen, respectively; a difference of 169,436 yen. Drug expenditure accounted for more than half of the medical costs for each group. The periods under mechanical ventilation management and in the ICU for the sivelestat group were shorter than those for the control group by 2 and 1.8 days, respectively. This was of significance in the reduction of the medical costs. A sensitivity analysis suggested that the expected costs for the sivelestat group exceeded those for the control group when the daily weaning rate for the sivelestat group was <3.5%, and also when mortality rates were set at 0.9% in the sivelestat group and 1.4% in the control group. CONCLUSIONS: This analysis suggests that from the Japanese healthcare payer perspective, treatment with sivelestat may reduce medical costs compared with standard care for patients with ALI associated with SIRS caused by infection.