Kerfuffle!

To become disheveled. A kerfuffle is the polite term for a cascading series of errors that can be initiated by a seemingly innocuous event that then leads to other errors that gain in severity and impact. This article describes some of the common kerfuffles that arise in modeling and simulation efforts. The process of eradicating or minimizing the impact of these pharmacometric kerfuffles begins with the recognition that the errors that contribute to the kerfuffle can and should be addressed systematically. They are not just an unpleasant aspect of the job that pharmacometricians must learn to live with in the conscientious execution of their work.

The cost-effectiveness of cefepime plus metronidazole versus imipenem/cilastatin in the treatment of complicated intra-abdominal infection.

BACKGROUND: Our objective was to compare the economic benefits of cefepime plus metronidazole with those of imipenem/cilastatin in the treatment of complicated intra-abdominal infections. METHODS: We used a retrospective analysis of clinical outcomes and health resource utilization data collected during a randomized, double-blind, multi-center clinical trial. Seventeen university-affiliated hospitals in the United States and Canada participated, as did 323 patients with complicated intra-abdominal infections. Decision analysis was conducted using a decision node of cefepime vs. imipenem, and chance nodes that included an Acute Physiology and Chronic Health Evaluation (APACHE) II score of #15 versus .15; a need for posttreatment surgical procedures; and clinical outcomes. Effectiveness of treatment was measured by differences in the length and cost of hospital stays, the number and cost of surgical procedures after treatment, cure rates, and the cost of antibiotics. Also evalulated were the incremental costs of cure (i.e., the costs of additional cures). RESULTS: Comparing cefepime plus metronidazole with imipenem/cilastatin, the expected cost of patient care was $8,218 versus $10,414, respectively, and the cost-effectiveness ratio per cure was $10,058 versus $13,685. For severely ill patients (APACHE II score .15), the expected cost was $12,962 versus $23,153, and the cost-effectiveness ratio per cure was $15,321 versus $64,313. CONCLUSIONS: Cefepime plus metronidazole was more cost-effective than imipenem/cilastatin in the treatment of complicated intra-abdominal infections, primarily because of fewer post-treatment surgical procedures and shorter hospital stays. The primary advantage accrued to severely ill patients who had an APACHE II score .15.

Gatifloxacin and the elderly: pharmacokinetic-pharmacodynamic rationale for a potential age-related dose reduction.

OBJECTIVES: Recently, anecdotal reports via the FDA's MedWatch reporting system have documented rare but serious hyperglycaemia in elderly patients receiving gatifloxacin. One possible factor contributing to these events may be gatifloxacin overexposure, resulting from age-related decreases in renal function in elderly patients predisposed to glycaemic alterations. These analyses examine gatifloxacin exposure in 10 patients with severe hyperglycaemia, provide a pharmacokinetic-pharmacodynamic (PK-PD) rationale for a potential age-related dose reduction to avoid high exposures, and evaluate the likely impact of such a dose reduction on clinical efficacy in this specific patient population. METHODS: First, a previously derived population pharmacokinetic model, with patient demographics, was used to estimate gatifloxacin AUC0-24 following a dosage regimen of 400 mg/24 h in 10 index patients with severe hyperglycaemia. Second, the population pharmacokinetic model and patient demographic data from 2696 patients aged > or =65 years from two New Drug Application (NDA) databases were used to estimate AUC0-24 following dosage regimens for gatifloxacin of 200 and 400 mg/24 h. Finally, Monte Carlo simulation was utilized to assess the probability of achieving PK-PD target exposures against Streptococcus pneumoniae in elderly patients using these regimens. RESULTS: The mean estimated AUC0-24 among severe hyperglycaemia cases was 74 mg.h/L (range 57-100). Gatifloxacin AUC0-24 exposures for the 400 mg regimen were predicted to be higher in patients aged > or =65 years and similar to the severe hyperglycaemia cases. The probability of AUC0-24 > or =60 and > or =70 in patients aged > or =65 years for the 200 mg regimen was 0.03 and <0.01, respectively, versus 0.51 and 0.35 for the 400 mg regimen, respectively. The probability of achieving PK-PD target exposures against S. pneumoniae in patients aged > or =65 years receiving the 200 mg regimen was 0.99. CONCLUSIONS: The probability of a patient aged > or =65 years having an AUC0-24 > or =60-70 mg.h/L is markedly lower following a 200 mg regimen relative to a 400 mg regimen, suggesting a decreased risk of severe hyperglycaemia in a predisposed patient. Moreover, a dose reduction does not appear to significantly modify the likelihood of achieving the PK-PD target of gatifloxacin against S. pneumoniae.