Professor Eun Kyoung Chung of the College of Pharmacy established guidelines for the appropriate dose and usage of cefazolin, an antibiotic for infectious diseases in obese patients with a high treatment failure rate

Professor Eun Kyoung Chung of the College of Pharmacy and the Department of Pharmacy Practice of the College of Pharmacy at Purdue University have prepared guidelines for the appropriate dose and usage of cefazolin, an antibiotic used in the treatment of infectious diseases in obese patients with a high treatment failure rate. The research results have been published online in International Journal of Antimicrobial Agents (IF=15.441, top 2.33% in JCR) under the title, “Population pharmacokinetics and pharmacodynamics of cefazolin using total and unbound serum concentrations in patients with high body weight.”

Treatment option for infectious disease in obese patients with a relatively high failure rate

As obesity is on the rise globally, it has been consistently reported to worsen the prognosis of various infectious diseases on skin and soft tissue (muscle, ligament, fat, blood vessel, tendon, fibrous tissue, synovial tissue, etc.) in addition to chronic diseases such as hypertension and diabetes. In fact, among the treatment of various infectious diseases, it is more difficult to treat obese patients than normal weight patients. The failure rate of antibiotic treatment in normal weight patients is only 32.8%, but in obese patients, this rate is almost 51%. It is time to apply appropriate antibiotic therapy that reflects the various physiological adversities accompanying obesity and the characteristics of individual patients.

However, deriving an appropriate antibiotic treatment regimen for obese patients who require infection treatment has little support from substantive clinical data as there are numerous variables to consider. In the case of obese patients, pharmacokinetic changes for each drug could be due to a myriad of physiological changes such as increase in body fat mass, change in body fluid volume, change in organ function such as kidney, and various variables such as individual patient characteristics. All these variables also affect the blood level of the drug.

The blood level of the drug significantly affects the therapeutic effect. If the blood level of antibiotics is lower than the target range, the risk of treatment failure increases. Professor Chung said, “In this study, we conducted a joint clinical study with our counterparts in the U.S., where obesity is emerging as a major social problem. The research compares obese patients requiring antibiotic cefazolin treatment with normal weight patients and analyzes the blood levels of cefazolin antibiotics over time and many patient variables that affect them.”

Analysis of diverse patient groups, from normal weight to morbidly obese patients
In a joint clinical study including Purdue University, the research team analyzed various patient groups ranging from normal weight patients to morbidly obese patients focusing on the blood non-protein-conjugated antibiotic concentration data that demonstrates antibacterial activity of cefazolin repeatedly administered to patients with infectious diseases. The research team analyzed this data through modeling and simulation to derive an appropriate cefazolin treatment regimen for obese patients. Professor Chung said, “To date, most population pharmacokinetic studies do not consider the protein binding rate of antibiotics and suggest appropriate dosing recommendations based on the total blood concentration. Based on the concentration, we suggested an appropriate drug regimen.”

As a result of the study, it was found that the blood level of cefazolin greatly changed depending on the patient's kidney function, weight, blood albumin concentration, and body mass index. In the case of obese patients, compared to normal weight patients, it was confirmed that the appropriate treatment target based on the concentration of non-protein conjugated antibiotics was reached through high-dose or prolonged intravenous infusion. In general, the usual dose of cefazolin is 1-2g. However, in the case of obese patients, it was necessary to administer 2-3g per dose to reach the appropriate treatment target. In the case of infections caused by some Gram-positive bacteria with high antibacterial sensitivity, appropriate treatment targets can be reached even if normal doses are administered to obese patients, so appropriate drug therapy for the individual patient's clinical situation can be established in consideration of the patient's physiological characteristics and the characteristics of the infectious bacteria.

“Pour great effort into the preparation process for international multi-institutional joint research”
Professor Chung introduced this study as a “research that we put a lot of effort into the preparation process.” It was a multi-center joint research in cooperation with American clinical centers including St. Francis Hospital and Methodist Hospital, and Professor Chung had to pay careful attention to the clinical design. She planned the research through numerous meetings and discussions. She explained, “Determining the sampling range of target patient body weight was a significant design hurdle for the clinical study. It was fortunate that a variety of patients were enrolled in the actual study, ranging from 60kg to over 300kg. In this research, various model structures were evaluated to select a model that showed the best fit by using both total blood drug concentration and non-protein-bound drug concentration.”

Professor Chung said, “As a result of the study, I felt the greatest sense of achievement and satisfaction when I applied pharmacometric modeling and simulation techniques to a small number of patients and prepared appropriate drug therapy recommendations that could be used in clinical settings.” In her previous studies, Professor Chung also established a population pharmacokinetic model for various antibacterial agents such as piperacillin/tazobactam, meropenem, and doripenem, and suggested appropriate antibiotic treatment regimens for obese patients compared to normal weight patients. The results of these studies were published in SCI-level journals and served as the basis for the development of antibiotic therapy integrated guidelines for adult obese patients published in 2017 and 2022. She said, “In the future, we will conduct extensive clinical studies to establish appropriate drug therapy guidelines by conducting clinical pharmacological modeling and simulation for various patient groups for which sufficient evidence has not been secured in pre-market clinical trials, not just obese patients. I want to improve performance and contribute to improving the quality of life of patients.”