Débora Cristina Sanches Pinto

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: 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.

Introduction: Faced with the growing challenge to the use of antimicrobials for the adequate and effective therapy of nosocomial infections, international health agencies have reinforced that combating bacterial resistance and preventing the development of multidrug-resistant (MDR) strains are urgent, since a significant increase based on minimum inhibitory concentration (MIC) for therapeutic agents were reported by the committee of hospitals infection. Meropenem, a carbapenem agent, is widely prescribed for therapy of septic shock caused by susceptible Gram-negative bacteria. In general, the prolonged 3-hrs-infusion has been widely applied in these patients over the past 10 years providing coverage only against susceptible Gram-negative pathogens (MIC 2 mg/L), extended also to intermediate susceptible strains up to MIC 4 mg/L, according to Clinical Laboratory Standard Institute (CLSI database). However, new strategies have been recommended to combat the development of resistance to pathogens isolated from cultures to increase the coverage of this carbapenem agent up to MIC 8 mg/L, to avoid mutant selection with death in ICU. Subject: Clinical protocol was carried out to investigate the efficacy & safety of meropenem at the dose regimen recommended 1g q8h by prolonged infusion, based on serum levels and on cultures monitoring of isolates. Aim of protocol was to assess pharmacodynamics (PD) based on changes of pharmacokinetics (PK), which could affect the coverage of meropenem in septic burns patients with increased or decreased renal function. Pharmacokinetic-pharmacodynamics (PK/PD) tools were applied to investigate efficacy & safety. Methods-clinical protocol: Forty-eight major septic burn patients with high variability on renal function in ICU were included. Cultures were collected before meropenem therapy starts; all of them had nosocomial infection caused by Gram-negative pathogens isolated. Patients undergoing meropenem therapy at the initial stage of septic shock from day-0 to day-8 (D0-D8) and at the late stage of septic shock from day 8 to day 14 (D-8 to D-14) were investigated according to dose requirements based on creatinine clearance, drug serum levels (TDM), and coverage up to MIC 8 mg/L, dose dependent on renal function. Results: Coverage occurred for all patients of both groups after the extended infusion against susceptible Gram-negative strains up to MIC 2 mg/L (minimum inhibitory concentration), and up to MIC 4 mg/L, strains of intermediate susceptibility, according to Clinical Laboratory Standards Institute (CLSI, database) of our hospital. It was demonstrated in patients with renal function augmented by vasopressors, the superiority on coverage by trice that occurred in 24/27 patients (89%) after 4 hrs.-infusion at TDM3 against strains MIC 8 mg/L by comparison with coverage registered in 12/39 patients (30%) after 3 hrs.-infusion at TDM2. On the other hand, meropenem dose regimen must be adjusted to 1g q24h in patients with AKI to guarantee effectiveness & safety in those patients. In addition, after continuous venovenous haemodialysis-filtration (CVVHDF) installed in those patients, meropenem PK/PD target was attained up to MIC 8 mg/L in patients with the empirical dose regimen recommended of 1g q8h, 3hrs.-infusion. Conclusion: Precision medicine guarantees meropenem serum levels combined with cultures monitoring; consequently, must be applied routinely to guarantee coverage against Gram-negative nosocomial pathogens susceptible including strains of intermediate susceptibility (MIC 4-8 mg/L) to avoid mutant selection. Therefore, effective, and safe antimicrobial therapy for patients in septic shock, combined with a continuous monitoring of inflammatory biomarkers, should guide clinical management to ensure cure with early ICU discharge.

Background and Aims: Skin grafting is the single most effective method to close a chronic wound. The current standard of care is to use meshed split thickness skin grafts. This entails the use of surgical instruments that need to be autoclaved and to have a power source, which usually requires an OR facility. The minced skin technique uses single use, presterilized instruments and the procedure can be done under local anesthesia, by a wound care practitioner, in a wound clinic, a physician's office or even at the bedside. The current study was designed to determine if the results from micrografting were non inferior to conventional mesh grafting.Methods: In a prospective non inferiority study, 26 chronic ulcers were treated with micrografting (MSG) and 24 with conventional mesh grafts 1:3 (control group‐CG) in a total of 21 patients, 10 male and 11 female. The donor site areas in the MSG group were predetermined to 2.5 × 5 cm and the mesh grafts expansion was set at 1:3.Results: In the first weeks postoperatively, micrograft healing initially lagged behind the conventional mesh grafts but at 60 days after grafting, all MSG wounds were healed. The MSG wounds had better pigmentation, less itching, and less scarring. The micrografting procedure was easy to learn and expeditious to perform. The MSG mean expansion was 9.1 compared to three times (CG).Conclusion: The MSG procedure is not inferior to conventional mesh grafting, requires smaller donor sites, and can be done with single use instruments, under local anesthesia, with early discharge.