Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria

Objectives: The aim was to analyse the population pharmacokinetics of colistin and to explore the relationship between colistin exposure and time to death. Methods: Patients included in the AIDA randomized controlled trial were treated with colistin for severe infections caused by carbapenem-resistant Gram-negative bacteria. All subjects received a 9 million units (MU) loading dose, followed by a 4.5 MU twice daily maintenance dose, with dose reduction if creatinine clearance (CrCL) 2 mg/L in 94% (195/208) and 44% (38/87) of patients with CrCL ≤120 mL/min, and >120 mL/min, respectively. Colistin methanesulfonate sodium (CMS) and colistin clearances were strongly dependent on CrCL. High colistin exposure to MIC ratio was associated with increased hazard of death in the multivariate analysis (adjusted hazard ratio (95% CI): 1.07 (1.03–1.12)). Other significant predictors included SOFA score at baseline (HR 1.24 (1.19–1.30) per score increase), age and Acinetobacter or Pseudomonas as index pathogen. Discussion: The population pharmacokinetic model predicted that >90% of the patients had colistin concentrations

Detrimental effect of apoptosis of lymphocytes at an early time point of experimental abdominal sepsis

<p>Abstract</p> <p>Background</p> <p>Apoptosis of lymphocytes is considered a late sequelum in the sepsis cascade. The role of apoptosis of lymphocytes as a driver of final outcome was investigated.</p> <p>Methods</p> <p>Abdominal sepsis was induced after cecal ligation and puncture (CLP) in 31 rabbits. Blood was sampled at serial time intervals and peripheral blood mononuclear cells (PBMCs) were isolated. Apoptosis of lymphocytes and monocytes was measured through flow cytometric analysis. PBMCs were stimulated with LPS and Pam3Cys for the release of tumor necrosis factor-alpha (TNFα). Tissue bacterial growth was quantitatively measured. In a second set of experiments, CLP was performed in another 40 rabbits; 20 received single intravenous infusions of ciprofloxacin and of metronidazole 4 hours after surgery.</p> <p>Results</p> <p>Animals were divided into two groups based on the percentage of lymphocyte apoptosis at 4 hours after surgery; less than or equal to 32% and more than 32%. Survival of the former was shorter than the latter (p: 0.017). Tissue growth was similar between groups. Apoptosis of lymphocytes and of monocytes was lower in the former group over follow-up. Release of ΤNFα did not differ. The above findings on survival were repeated in the second set of experiments. Administration of antimicrobials prolonged survival of the former group (p: 0.039) but not of the latter group (pNS).</p> <p>Conclusions</p> <p>Lymphocyte apoptosis at an early time point of experimental peritonitis is a major driver for death. A lower percentage of apoptosis leads earlier to death. Antimicrobials were beneficial even at that disease state.</p

Molecular diagnosis of sepsis

Introduction: Current management of sepsis relies on the early detection and early administration of antimicrobials. This requires detection of pathogens earlier than conventional blood cultures and recognition of the immune status of the host earlier than the conventional biomarkers. This can be achieved by molecular techniques. Areas covered: Molecular diagnosis of pathogens is based on either rapid detection of pathogens grown in blood cultures or direct use of whole blood and blood products. Molecular diagnosis of the constellation of activations and inhibitions of pathways implicated in cellular processes can be achieved by gene profiling of a large array of genes. Expert opinion: Molecular microbial diagnosis enables rapid identification and precedes results obtained by conventional culture methods. Its role can be proved more useful in sepsis caused by specific microorganisms such as fungi performed by PMA-FISH and MALDI-TOF MS. Molecular techniques using blood aim for rapid pathogen identification. However, the provided information regarding the antimicrobial susceptibility of the pathogen is limited. Gene profiling in sepsis provides individualized information for the activation or inhibition of pathways of a variety of cellular processes. The transcriptome information is difficult to interpret in everyday clinical practice particularly on how information translates to patient needs. © 2012 Informa UK, Ltd

Emerging drugs for the treatment of sepsis

Introduction: Despite improvement in medical care, severe sepsis and septic shock remain an unmet medical need. Their incidence is steadily increasing and the worldwide mortality ranges between 30% and 50%. This generates the need for agents that modulate the immune function of the host. Areas covered: Available agents can be divided into three categories according to their mechanism of action: i) agents that block bacterial products and inflammatory mediators. Hemoperfusion with polymyxin B embedded fiber device that blocks bacterial lipopolysaccharides (LPS) has given promising clinical results. Blockade of TNF-α with afelimomab and CytoFab appears promising; ii) modulators of immune function. Hydrocortisone stress replacement, intravenous infusion of clarithromycin and immunonutrition with omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) have all yielded positive clinical results. Recombinant thrombomodulin for patients with disseminated intravascular coagulation appears a promising alternative; and iii) immunostimulation. Meta-analysis of conducted trials disclosed the decrease of mortality in septic shock after administration of immunoglobulin preparations enriched with IgM. Expert opinion: The underlying pathophysiologic mechanisms in septic patients are highly individualized. As such, specific tools should be developed in the near future to define these differences and tailor therapeutic strategies accordingly. © 2012 Informa UK, Ltd

Meropenem-vaborbactam: a critical positioning for the management of infections by Carbapenem-resistant Enterobacteriaceae

Introduction: The review aims to review the positioning of meropenem-vaborbactam in clinical practice, taking into consideration the characteristics of other available drugs, namely ceftazidime-avibactam, plazomicin, and colistin. Areas covered: The search terms ‘meropenem-vaborbactam’ or RX7009 for the years 2006 until 2021 were used. Expert opinion: Coupling of meropenem with the cyclic boronate derivative varobactam enhances considerably the in vitro intrinsic activity of meropenem against isolates producing KPC (Klebsiella pneumoniae-producing carbapenemase). The drug has linear elimination and the ratio of the area under the curve of the free drug to the minimum inhibitory concentration is the main pharmacodynamics variable determining bacterial clearance. Meropenem-vaborbactam is currently approved for the management of complicated urinary tract infections including acute pyelonephritis, complicated intraabdominal infections, and hospital-acquired pneumonia including ventilator-associated pneumonia. © 2022 Informa UK Limited, trading as Taylor &amp; Francis Group

An early circulating factor in severe sepsis modulates apoptosis of monocytes and lymphocytes

We hypothesized that a factor may circulate in serum early during sepsis, modulating apoptosis of monocytes and lymphocytes. Serum was collected from 20 healthy volunteers and from 48 patients with severe sepsis/ shock within 12 h from signs of the first failing organ. PBMCs were isolated from 20 healthy volunteers and incubated with collected sera. Apoptosis and expression of CD95 were determined by flow cytometry; experiments were run in the presence of caspase-8 and caspase-9 inhibitors and of CaCl2. Activity of caspase-3 was determined in cell lysates by a chromogenic kinetic assay. Incubation with serum of patients induced apoptosis of CD4 lymphocytes and inhibited apoptosis of CD14 monocytes. This was attenuated after diluting serum or mixing with healthy serum. Activity of caspase-3 was consistent with these findings. Induced apoptosis of CD4 lymphocytes was greater among nonsurvivors, and it was inhibited in the presence of caspase inhibitors. Inhibitors did not modify the effect of patients&apos; serum on apoptosis of CD14 monocytes. CaCl 2 reversed the inhibitory effect on apoptosis of CD14 moncytes. The above findings support the hypothesis for the existence of an early circulating factor in severe sepsis/shock, modulating apoptosis of CD4 lymphocytes and of CD14 monocytes by interaction with the two apoptotic pathways. © Society for Leukocyte Biology