Previous studies have clearly demonstrated a significant impact of optimised antibiotic therapy based on a TDM-guided approach in reducing the clinical and microbiological failure rate and in improving the achievement of an optimal pharmacokinetic/pharmacodynamic target. However, no study has yet evaluated this aspect in the specific scenario of liver transplant patients with documented infections with Gram-negative pathogens.
adult OLT recipients (age ≥ 18 years);
documented Gram-negative infections occurring in the first 90 days after transplantation;
treatment with beta-lactam based-regimens;
signed informed consent.
patients receiving beta-lactam-based regimens for less than 48 hours;
patients with isolation of a Gram-negative resistant to all available beta-lactam classes;
patients on palliative care and/or not resuscitation order.
All consecutive adult OLT recipients admitted to the Internal Medicine ward of the IRCCS Azienda Ospedaliero-Universitaria di Bologna for the treatment of severe organ failure who will be scheduled for liver transplantation will be enrolled in the study at the time of liver transplant.
Cohort
Prospective
Not listed
Verify if the attainment of optimal beta-lactam PK/PD targets improves the rate of microbiological eradication in OLT recipients with documented Gram-negative infections
Microbiological eradication, defined as the absence of the index pathogen from the primary site of infection in at least two subsequent assessments Dichotomous variable (yes/no)
Verify if the attainment of optimal beta-lactam PK/PD targets improves the rate of clinical cure in OLT recipients with documented Gram-negative infections
Clinical cure, defined as complete resolution of signs and symptoms of the infection coupled with documented microbiological eradication at the end of treatment and the absence of recurrence or relapse at 30-day Dichotomous variable (yes/no)
To identify factors independently predicting failure in attaining early optimal beta-lactam PK/PD targets
Optimal beta-lactam PK/PD targets will be defined as follows \[23\]: 1. For beta-lactams not coupled with beta-lactamase inhibitors (i.e., cefepime, ceftazidime, meropenem, and cefiderocol): * Optimal: steady state concentrations (Css)/MIC ratio \> 4 * Quasi-optimal: Css/MIC ratio = 1-4 * Suboptimal: Css/MIC ratio \< 1 2. For beta-lactam coupled with beta-lactamase inhibitors (i.e., piperacillin-tazobactam, ceftolozane-tazobactam, ceftazidime-avibactam, and meropenem-vaborbactam): * Optimal: a Css/MIC ratio \> 4 for beta-lactam coupled with the attainment of an optimal threshold for beta-lactamase inhibitors (Css/threshold concentration \[CT\] ratio \> 1 for tazobactam and avibactam, or AUC/MIC \> 24 for vaborbactam). * Quasi-optimal: only one of the two optimal thresholds are attained. * Suboptimal: none of the two optimal thresholds are attained.
To identify the relationship between the attainment of optimal beta-lactam PK/PD targets and antibiotic resistance development and post-OLT MDR colonization occurrence at 90-days
Resistance development, defined as an MIC increase of the selected beta-lactam against the clinical isolate beyond the EUCAST clinical breakpoint of susceptibility Dichotomous variable (yes/no) MDR colonization at 90-day, defined as the occurrence of a novel colonization by carbapenemase-producing Enterobacterales or carbapenem-resistance Acinetobacter baumannii at 90-day after starting beta-lactam therapy Dichotomous variable (yes/no)
To identify the association between the attainment of optimal PK/PD targets for beta-lactams and variation of inflammatory biomarkers (C-reactive protein [CRP], procalcitonin [PCT], and pro-/anti-inflammatory cytokines
To identify the association between the attainment of optimal PK/PD targets for beta-lactams and variation of inflammatory biomarkers (C-reactive protein \[CRP\], procalcitonin \[PCT\], and pro-/anti-inflammatory cytokines, namely IL-6, IL-1, IL-12, IL-8, IL-10, and TNF-α); Relative variation (delta) Continuous variable (numerical)
To evaluate the attainment of optimal beta-lactams PK/PD targets at the site of infection in case of pneumonia, intrabdominal and/or biliary infections
Optimal beta-lactam PK/PD targets will be defined as follows \[23\]: 1. For beta-lactams not coupled with beta-lactamase inhibitors (i.e., cefepime, ceftazidime, meropenem, and cefiderocol): * Optimal: steady state concentrations (Css)/MIC ratio \> 4 * Quasi-optimal: Css/MIC ratio = 1-4 * Suboptimal: Css/MIC ratio \< 1 2. For beta-lactam coupled with beta-lactamase inhibitors (i.e., piperacillin-tazobactam, ceftolozane-tazobactam, ceftazidime-avibactam, and meropenem-vaborbactam): * Optimal: a Css/MIC ratio \> 4 for beta-lactam coupled with the attainment of an optimal threshold for beta-lactamase inhibitors (Css/threshold concentration \[CT\] ratio \> 1 for tazobactam and avibactam, or AUC/MIC \> 24 for vaborbactam). * Quasi-optimal: only one of the two optimal thresholds are attained. * Suboptimal: none of the two optimal thresholds are attained.
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