meropenem and Inflammation

The purpose of this study was to explore factors influencing meropenem pharmacokinetics (PKs) in critically ill patients by developing a population PK model and to determine the optimal dosing strategy.. This prospective observational study involved 12 critically ill patients admitted to the intensive care unit and treated with meropenem 1 g infused over 1 h every 8 h. Blood samples were collected on days 1, 2, and 5 immediately prior to dosing, and at 1, 2, 4, and 6 h after the start of infusion. Population PK parameters were estimated using nonlinear mixed-effects model software.. Meropenem PK was adequately described using a two-compartment model. Typical values of total and inter-compartmental clearance were 9.30 L/h and 9.70 L/h, respectively, and the central and peripheral compartment volumes of distribution were 12.61 L and 7.80 L, respectively. C-reactive protein (CRP) was identified as significant covariate affecting total meropenem clearance. The probability of target attainment (PTA) predicted by Monte Carlo simulations varied according to the patients' CRP. The PTA of 100% time above the minimum inhibitory concentration ≤2 mg/L for bacteria was achieved after a dose of 1 and 2 g infused over 4 h every 8 h in patients with CRP of 30 and 5 mg/dL, respectively.. The findings of this study suggest that CRP might be helpful in managing meropenem dosing in critically ill patients. Higher doses and extended infusion may be required to achieve optimal pharmacodynamic targets.

Topics: Anti-Bacterial Agents; Critical Illness; Humans; Inflammation; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method

Topics: Animals; Anti-Bacterial Agents; Inflammation; Kidney; Liver; Meropenem; Rats; Shock, Septic

Topics: Antifungal Agents; Humans; Inflammation; Meropenem; Renal Insufficiency; Voriconazole

Topics: Adult; Allografts; Anastomosis, Surgical; Aneurysm, Infected; Gout; Humans; Hyperuricemia; Iliac Artery; Inflammation; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Meropenem; Postoperative Complications; Renal Artery; Teicoplanin; Thienamycins; Treatment Outcome

Severe sepsis remains a poorly understood systemic inflammatory condition with high mortality rates and limited therapeutic options in addition to organ support measures. Here we show that the clinically approved group of anthracyclines acts therapeutically at a low dose regimen to confer robust protection against severe sepsis in mice. This salutary effect is strictly dependent on the activation of DNA damage response and autophagy pathways in the lung, as demonstrated by deletion of the ataxia telangiectasia mutated (Atm) or the autophagy-related protein 7 (Atg7) specifically in this organ. The protective effect of anthracyclines occurs irrespectively of pathogen burden, conferring disease tolerance to severe sepsis. These findings demonstrate that DNA damage responses, including the ATM and Fanconi Anemia pathways, are important modulators of immune responses and might be exploited to confer protection to inflammation-driven conditions, including severe sepsis.

Topics: Adenoviridae Infections; Animals; Anthracyclines; Anti-Bacterial Agents; Ataxia Telangiectasia Mutated Proteins; Autophagy-Related Protein 7; Cecum; DNA Damage; DNA Repair; Epirubicin; Fanconi Anemia Complementation Group D2 Protein; Inflammation; Inflammation Mediators; Injections, Intraperitoneal; Lung; Meropenem; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Organ Specificity; Peritonitis; Respiratory Tract Infections; Sepsis; Shock, Septic; Thienamycins; Whole-Body Irradiation

Procalcitonin (PCT) is an early marker of bacterial infection but little is known about its value in neutropenic allogeneic bone marrow transplant (BMT) recipients. We collected plasma from 12 recipients of T-cell-depleted HLA-matched related BMT recipients who had been treated preemptively with meropenem from the day after BMT for at least 15 days. PCT and C-reactive protein (CRP) concentrations were determined on BMT days 1, 5, 8, 12, and 15, and their relationship to inflammatory events (IE), including mucositis, microbiologically and clinically defined infections, acute graft-versus-host disease (GVDH), and unexplained fever, was then determined. The PCT concentrations were all low and never exceeded 4 microg/liter, unlike CRP concentrations, which spanned the full range up to 350 mg/liter. All patients had mucositis, and there was no significant difference between PCT concentrations associated with mucositis alone and those associated with an additional IE on BMT days 1 to 12. However, on BMT day 15, the mean concentrations of PCT were 0.37 +/- 0.05 microg/liter for the 10 patients that had an additional IE, compared with 0.11 +/- 0.03 microg/liter for the 2 patients with mucositis only (P = 0.012), and GVHD rather than infection was involved in six cases. PCT was also not a sensitive marker of gram-positive bacteremia or pulmonary aspergillosis. Thus, PCT is of little value in discriminating infections from other inflammatory complications that occur following allogeneic BMT.

Topics: Adult; Biomarkers; Bone Marrow Transplantation; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Diagnosis, Differential; Female; Graft vs Host Disease; Humans; Infections; Inflammation; Male; Meropenem; Protein Precursors; Thienamycins; Transplantation, Homologous

In a rabbit Escherichia coli meningitis model, endotoxin liberation and concentrations of leukocytes, tumor necrosis factor (TNF), and lactate were compared after a single intravenous dose of cefotaxime, cefpirome, meropenem, chloramphenicol, or gentamicin. These antibiotics caused a 2- to 10-fold increase in cerebrospinal fluid concentrations of free (filterable) endotoxin within 2 h of starting treatment. By contrast, free endotoxin concentrations increased almost 100-fold in untreated animals 4 h later as bacteria continued to multiply. An initial enhancement of inflammation in the central nervous system occurred in all treatment groups compared with untreated controls. No significant differences were observed between treatment groups except for lower TNF concentrations in chloramphenicol-treated animals. Antibiotic therapy in E. coli meningitis, irrespective of the agent used, may result in an increase in free endotoxin and enhancement of inflammation, but the amount of endotoxin liberated is considerably smaller than that shed by untreated bacteria.

Topics: Animals; Anti-Bacterial Agents; Cefotaxime; Cefpirome; Cephalosporins; Chloramphenicol; Endotoxins; Escherichia coli Infections; Gentamicins; Inflammation; Male; Meningitis, Bacterial; Meropenem; Rabbits; Thienamycins

The pharmacokinetics and penetration into a cantharidine-induced inflammatory exudate of meropenem was studied in six volunteers following a single 1-g intravenous dose. Concentrations in plasma, urine, and the inflammatory exudate were determined by a microbiological assay. The mean elimination half-life of meropenem in plasma was 1.1 h, with the concentration in plasma declining from a mean of 23.6 micrograms/ml at 1 h to 0.7 micrograms/ml at 6 h. The inflammatory fluid penetration was rapid (time to maximum concentration of drug in serum, 0.75 h), and the penetration was 111%. The recovery of meropenem in urine at 24 h was 65.4% of the administered dose.

Topics: Adult; Exudates and Transudates; Half-Life; Humans; Inflammation; Male; Meropenem; Thienamycins