Pharmacokinetic/pharmacodynamic (PK/PD) principles in monitoring beta-lactam antibiotics in critically ill patients : evaluating the current approach, knowledge, perception, and prescribing practice of clinicians

Abstract

Infection is an independent factor associated with increased mortality in the intensive care unit (ICU). To manage such problem, antibiotics are utilized. It is argued that current antibiotic dosing approach is not sufficient for patients in the ICU due to significant pathophysiological changes. Different ICUs might employ different antibiotic dosing approach based on local guidelines and practice. Malaysia already has two published guidelines on managing infection in the ICU but data on its compliance is largely unknown. This study aimed to determine clinicians' knowledge and perception on antibiotic pharmacokinetic/pharmacodynamic (PK/PD) and its integration in antibiotic dosing, and practice of antibiotic prescribing among clinicians in the ICU. This study also investigating whether contemporary antibiotic dosing used in the ICU is adequate in achieving the recommended PK/PD target. This study consisted of two parts with both occurring simultaneously. The first part was a cross-sectional online survey among anesthesiologists, intensivists, Infectious Disease Specialists, and other specialists working primarily in the ICU. The survey consisted of 3 sections: knowledge, perception, and antibiotic prescribing practice among clinicians in ICU. The second part was a prospective, PK/PD point prevalence study involving beta-lactam antibiotics conducted in the ICU of three teaching hospitals. Two blood samples were taken from each patient during a single dosing interval. Antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at mid-point (50% fT>MIC), end of dosing interval (100% fT>MIC), and 100% fT>4xMIC (four times the concentration above the MIC at end of dosing interval) were set as the PK/PD target. Data were analyzed descriptively for Study Part One, and multiple logistic regression was used to describe effect of antibiotic exposure on patient outcomes in Study Part Two. All data analyses were conducted using IBM SPSS Statistics 22 (IBM Corporation, Armonk, New York). A total of 104 respondents completed the survey in part one and they concurred the importance of PK/PD in antibiotic optimization. Majority (97.2%) perceived that current dosing of antibiotics is inadequate to achieve optimal PK/PD target in ICU patients. Most (85.6%) believed that antibiotic dose should be streamlined to the organisms’ MIC. Adherence rates in terms of antibiotic choices with established guideline were at 79.8%, 77.8%, and 27.9% for HAI, INP, and CRBSI, respectively. In part two, 101 patients were recruited. The median Sequential Organ Failure Assessment score was 7 (interquartile range [IQR], 4-9). Majority of patients was able to achieved the minimum PK/PD target of 50% fT>MIC and 100% fT>MIC (88.1% and 73.3% respectively) but when the target was set higher at 100% fT>4xMIC, only one-third (34.7%) of patients met the outcome. Continuous infusion was associated with higher attainment of PK/PD ratio of plasma concentration and pathogen’s MIC (P = 0.07). Achieving a high serum concentration of beta-lactam antibiotics at mid dosing interval was 4% more likely to have better mortality outcomes (P = 0.045). Clinicians in the ICU are receptive to employ PK/PD approach in optimizing antibiotic dosing for critically ill patients but are limited by gaps in the knowledge of antibiotic PK/PD. Survivability of sepsis patients is significantly improved when serum concentration of beta-lactam antibiotics at mid-point dosing interval is high.