Combined antimicrobial therapy in septic major burns based on drug serum levels and cultures to combat bacterial resistance by pharmacokinetics based on pharmacodynamics

Introduction: Vancomycin and piperacillin-tazobactam are widely prescribed in the therapy of septic shock of critically ill ICU patients, including major burns with infections caused by susceptible Gram-positive and Gram-negative nosocomial bacteria. Therapeutic drug serum monitoring and cultures were essential to combat these infections. Therefore, combating the development of resistance is a relevant first-line tool to ensure the maintenance of these antibiotics in the therapeutic arsenal, especially in tertiary public hospitals with high demand for care for these septic patients with high-risk mortality admitted to Intensive Care Units. Subject: Aim of the study was investigated by an open label clinical protocol in major burns during the first septic shock, after 72 hours of ICU admission to evaluate pharmacodynamics based on pharmacokinetics, that could affect the coverage of vancomycin, 1-hr. intermittent infusion, in a combined therapy with piperacillin-tazobactam by 3-hrs.-extended infusion in a dose prescribed in a creatinine clearance dependence, against susceptible pathogens. Methods: The primary endpoint was the pharmacodynamics target based on microbiology of the isolate susceptible strains obtained from cultures, and on drug serum monitoring that was realized by two Sets of blood sampling for antibiotics serum measurements by TDM, twice a week, to reach the target recommended for both ATBs, with dose prescribed based on a renal function dependence. The recommended target for vancomycin by 1hr. intermittent infusion was considered against Gram-positive susceptible strains; while for piperacillin-tazobactam by 3hrs.-extended infusion was chosen against Gram-negative strains. The primary outcome was to evaluate the combined therapy prescribed to patients, considering vancomycin and piperacillin/tazobactam dose prescribed in Set 1 at TDM1 vs Set 2 at TDM 2, adjusted or maintained dose. Results: Coverage strategy was based on the prediction index (AUCss0-24/MIC, ratio) for vancomycin effectiveness related to target attainment. In addition, coverage related to piperacillin-tazobactam was based on the prediction index of drug effectiveness (%f T>MIC) based on target attainment. It is important to highlight that each antibiotic coverage was monitored at the first septic shock, in the early stage in patients with high variability of renal clearance as acute kidney injury (AKI, n=10), renal function preserved or vasopressor requirements (n=22). PK-changes impacted coverage of both ATBs related to renal function dependence by each antibiotic investigated, and dose adjustment was done in real time for each patient. Conclusion: Combined therapy of septic shock with vancomycin-piperacillin/tazobactam against nosocomial pathogens by PK/PD approach was done twice a week based on cultures, ATBs serum levels to guarantee the target attainment in a short period for all patients. Then, this strategy has been applied in the last ten years in the clinical protocols of our hospital, especially in the ICU of Burned Unit, to guarantee the individualized therapy by antimicrobial coverage, that contributes for combating the mutant´s selection of Enterobacteriaceae. and to prevent the development of bacterial resistance resulting in death on ICU by selection of MDR pathogens.