Maria Severina dos Santos

Introduction: Septic shock is a preventable event caused by potentially fatal organ dysfunction due to a dysregulated host response to infection. Thus, the clinical outcome in most high-risk cases is death in ICU patients with nosocomial bacterial infections, most often associated with renal failure, receiving therapy with hydrophilic antibiotics against Gram-negative or Gram-positive bacteria to combat the development of multidrug resistance. Furthermore, mortality due to the high incidence of Gram-negative bacterial (GNB) infections in ICU patients has not improved over the past 20 years against nosocomial pathogens, which typically present positive cultures by the end of the first week up to second week of ICU admission. Consequently, increased mortality has been linked to the lack of therapeutic serum monitoring of hydrophilic antibiotics in patients at the bedside in ICUs with failure of therapy. Therefore, dosing regimen should be individualized based on renal function by applying the recommended biomarkers. Subject: Aim of the study was to investigate ICU patients with severe burns during the septic shock undergoing meropenem individualized therapy to investigate if changes on pharmacokinetics (PK) occurs in a renal function dependence with impact on pharmacodynamics (PD), once target attainment against meropenem susceptible strains up to MIC/MIC was attained against susceptible strains up to MIC 2 mg/L for 18/24 patients with renal function augmented by vasopressors during the systemic inflammatory response syndrome, while 1g q6h was required to the rest of them (6/24) to guarantee coverage. In addition, an acute kidney injury occurred during septic shock, and daily dose must be reduced to 1g q24h to guarantee safety and effectiveness. Finally, continuous renal replacement therapy (CRRT) during the acute kidney injury (creatinine clearance lower than 20 ml/min); consequently, dose adjustment (1g q12h) was required to guarantee coverage. During CRRT preserved renal function was restorage, and negative cultures occurred. Conclusion: Pharmacodynamics based on pharmacokinetic changes in ICU patient/bedside offers an essential tool for combating microbial resistance against nosocomial pathogens, based on drug serum levels and cultures data for individualized therapy done in real time. This strategy was applied to ensure individualized for dosing improved outcomes in 83% of patients, which contributed to combating the selection of nosocomial MDR- GNB.

Introduction: The incidence of nosocomial infections in the ICU and mortality in critically ill septic patients have not improved over the past 15 years against Gram-negative strains with incidence after 72 hours of hospital admission. It has been widely reported that increased mortality in the ICU is associated with the lack of serum antibiotic monitoring that is necessary for dose adjustment; particularly in acute kidney injury (AKI) and during continuous Veno-venous hemodialysis filtration (CVVHDF) in those patients. Subject: The study aims to investigate patients with severe septic burns during second or third septic shock undergoing individualized Meropenem therapy regarding changes in pharmacokinetics (PK) that impact pharmacodynamics (PD) based mainly on coverage against susceptible Gram-negative nosocomial pathogens. Methods: Twenty-nine patients included in the protocol were distributed in three groups. Meropenem was chosen to ensure coverage against non-Enterobacteriaceae as Pseudomonas aeruginosa, which occurs from the second septic shock in ICU patients with severe burns, and even for coverage against Enterobacteriaceae nosocomial strains. Two blood samples were required for each TDM set and PK study; another blood sampling was done for biomarkers monitoring. One compartment open model was chosen for PK-study; pharmacokinetics of meropenem were based on blood sampling and drug serum measurements by HPLC. Target recommended against non-Enterobacteriaceae & Enterobacteriaceae of 100%fDT>MIC was based on pharmacokinetic changes that could impacts pharmacodynamics of isolated strains by cultures monitoring, and by MIC data (CSLI). Non-parametric tests were applied, and the significance of p<0.05 was considered. Results: Meropenem target recommended was attained against susceptible strains up to MIC 2 mg/L and dose adjustments required were based on renal function reduced in 24/29 patients of G1-G2 with acute kidney injury (AKI) and followed by continuous Veno-venous hemodialysis filtration (CVVHDF) installed. Coverage against non-Enterobacteriaceae and Enterobacteriaceae occurred up to MIC 2 mg/L susceptible strains, and it was extended up to MIC 4 mg/L for 24 patients of G1-G2. Inflammatory biomarkers (SIRS), such as c-RP and N/L ratio were investigated. A significant difference was demonstrated between 24/29 survivors (83%) and 5/29 non-survivors (17%), who died within 10 to 12 days of Meropenem therapy, related to the (N/L) ratio predicting mortality. Conclusion: Therapy of septic shock with Meropenem was effective against Gram-negative nosocomial pathogens considering PK/PD analysis done weekly based on TDM, cultures monitoring, and N/L ratio as a predictive biomarker of mortality.

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.

Introduction: Septic shock is one of the leading causes of death among critically ill patients in the Intensive Care Unit (ICU), including severely major burned patients. Rapid diagnosis and early initiation of effective antimicrobial therapy are the main challenges. The role of leukocytes as the neutrophil/lymphocyte ratio (NLR) and various systemic inflammatory indices, include serum levels of interleukin-6 (IL-6), procalcitonin (PCT) and c-reactive protein (c-RP) are the informative laboratory markers in this regard respect. Subject: Monitoring of serum levels of interleukin (IL6), procalcitonin (PCT) and C-reactive protein (C-RP), including among leukocytes the index neutrophil/lymphocyte ratio (NLR), proposed previously, investigated at the first septic shock of major burns undergoing meropenem therapy recommended in hospital, during the systemic inflammatory response syndrome (SIRS), after ICU admission. Fundamental aim of study was to investigate the relationship, and contribution of these biomarkers at the early versus late stage of septic shock, as well as to determine the diagnostic performance of them in major burn patients that could impact outcome. Methods: In this prospective open label study, a total of 30 major septic burn patients with renal function preserved, augmented or with acute kidney injury (AKI) was enrolled at the first septic shock after accident and ICU admission, based on systemic inflammatory response syndrome (SIRS) criteria. All patients had been selected from the ICU of Plastic Surgery and Burn Unit of tertiary public hospital of Medical School, University of Sao Paulo, SP, Brazil. Laboratory data with known clinicopathological parameters were recorded. Serum levels of IL6, PCT, c-RP and NLR from the blood count were evaluated. Inflammatory biomarkers such as c-RP, PCT and IL6 in serum were performed on the COBAS 8000 series (c-RP) or COBAS E411 series analyzer for PCT, IL6 (Roche, registered trademark), neutrophil to lymphocyte ratio (blood count) was measured using a Hematology Analyzer (SYSMEX brand). Therapeutic serum measurements of combined therapy with antibiotics (ATB) were done by comparison of coverage at the earlier versus late stage of septic shock. Results: A significant difference was found in NLR, IL6, PCT and c-RP in surviving patients (n=20) comparing data obtained in early stage versus late-stage SIRS (p<0.05) in major burns with positive bacteriological cultures. On the other hand, there was no significant difference between the NLR and IL6 periods, which occurred when comparing data in the early versus late stage of SIRS in non-survival patients, who died between 7 and 10 days of antimicrobial therapy. There was an increasing trend in serum levels of NLR and IL6, PCT and c-RP in large burns, dependent on the timing of septic shock stages, with diagnostic value as early appearance of biomarkers. On the other hand, we recorded that the association of NLR and IL6 produces better diagnostic value in predicting ICU mortality than PCT or c-RP. Conclusion: It was shown in this pilot study that elevated NLR and increasing serum levels of IL6, PCT, c-RP occurred during SIRS in septic patients’ major burns. So, the combined use of these biomarkers may play a potential role in the early diagnosis of septic shock for adequate initial therapy of these ICU patients. Combined biomarkers (NLR-IL6) can further predict ICU mortality of septic patients with acute kidney injury occurring during SIRS. Finally, a prospective multicenter study in a large cohort can be performed to confirm the data obtained in this investigation.