Eleni Boutzouka

Colistin serum concentrations after intravenous administration in critically ill patients with serious multidrug-resistant, gram-negative bacilli infections: a prospective, open-label, uncontrolled study.

BACKGROUND The emergence of multidrug-resistant nosocomial pathogens, such as Pseudomonas aeruginosa and Acinetobacter baumannii, has led to the revival of the systemic use of antimicrobial agent colistin in critically ill patients, but only limited data are available to define its pharmacokinetic profile in these patients. OBJECTIVE The aim of this study was to assess steady-state serum concentrations of colistin after i.v. administration of colistin methanesulfonate (CMS) in critically ill patients with stable kidney function. METHODS This prospective, open-label, uncontrolled study was conducted at 2 intensive care units in the Athens Trauma Hospital, KAT, Athens, Greece. Adult patients were nonconsecutively enrolled if they were critically ill and had stable kidney function (<0.5 mg/dL change in serum creatinine prior to and until the day of sample collection) and had been receiving CMS as part of a treatment regimen for sepsis irrespective of site of infection with multidrug-resistant, gram-negative bacilli. After i.v. administration of 225-mg CMS (with the exception of 1 patient who received 150 mg) every 8 or 12 hours for at least 2 days, blood samples were collected just before and at 10 minutes and 1, 2, 4, 6, and 8 hours after i.v. infusion (duration, 30 minutes) of the colistin dose on the sampling day. RESULTS Fourteen nonconsecutive patients were enrolled in the study (13 male, 1 female; mean [SD] age, 62.0 [19.2] years; mean [SD] estimated weight, 72.5 [8.5] kg; mean [SD] Acute Physiology And Chronic Health Evaluation II score on admission, 17.1 [6.0]). At steady state, mean (SD) colistin maximum and minimum concentrations were 2.93 (1.24) and 1.03 (0.44) mg/L, respectively, while mean (SD) apparent total body clearance, apparent volume of distribution, and t(1/2) were 13.6 (5.8) L/h, 139.9 (60.3) L, and 7.4 (1.7) hours, respectively. Colistin-related nephrotoxicity was not observed in the study patients. CONCLUSION CMS dosage regimens administered to these critically ill adult patients were associated with suboptimal Cmax/MIC ratios for many strains of gram-negative bacilli currently reported as sensitive (MIC, < or = 2 microg/mL).

Serum and Cerebrospinal Fluid Concentrations of Linezolid in Neurosurgical Patients

ABSTRACT Linezolid is a new antimicrobial agent effective against drug-resistant gram-positive pathogens commonly responsible for central nervous system (CNS) infections in neurosurgical patients hospitalized in intensive care units. In order to study the penetration of this antimicrobial into the cerebrospinal fluid (CSF) of such patients, the disposition of linezolid in serum and CSF was studied in 14 neurosurgical patients given linezolid at 600 mg twice daily (1-h intravenous infusion) for the treatment of CNS infections caused by gram-positive pathogens or for prophylactic chemotherapy. Serum and CSF linezolid steady-state concentrations were analyzed by high-pressure liquid chromatography, and the concentration-time profiles obtained were analyzed to estimate pharmacokinetic parameters. The mean ± standard deviation (SD) linezolid maximum and minimum measured concentrations were 18.6 ± 9.6 μg/ml and 5.6 ± 5.0 μg/ml, respectively, in serum and 10.8 ± 5.7 μg/ml and 6.1 ± 4.2 μg/ml, respectively, in CSF. The mean ± SD areas under the concentration-time curves (AUCs) were 128.7 ± 83.9 μg · h/ml for serum and 101.6 ± 59.6 μg · h/ml for CSF, with a mean penetration ratio for the AUC for CSF to the AUC for serum of 0.66. The mean elimination half-life of linezolid in CSF was longer than that in serum (19.1 ± 19.0 h and 6.5 ± 3.6 h, respectively). The serum and CSF linezolid concentrations exceeded the pharmacodynamic breakpoint of 4 μg/ml for susceptible target pathogens for the entire dosing interval in the majority of patients. These findings suggest that linezolid may achieve adequate concentrations in the CSF of patients requiring antibiotics for the management or prophylaxis of CNS infections caused by gram-positive pathogens.

Colistin pharmacokinetics in intensive care unit patients on continuous venovenous haemodiafiltration: an observational study

OBJECTIVES Available data on colistin pharmacokinetics in patients undergoing continuous renal replacement therapy (CRRT) are limited. Our aim was to study colistin pharmacokinetics in critically ill patients treated with colistin methane sulphonate for Gram-negative sepsis and undergoing continuous venovenous haemodiafiltration for acute renal failure. PATIENTS AND METHODS Three patients were studied. The colistin methane sulphonate dose administered was at the discretion of the attending physician and was in all cases lower than that recommended for individuals with intact renal function. Colistin methane sulphonate was administered intravenously over 30 min, and blood samples were collected from each patient pre- and post-filter for the HPLC determination of colistin levels in serum before infusion, at 10, 60, 120, 240, 360, 480 and 600 min from the end of infusion, and immediately before the next dose. Concurrently, spot samples of effluent from the haemofilter were also collected and analysed. Both colistin total extracorporeal clearance and clearance in the effluent were calculated. RESULTS Extracorporeal clearance resulted in substantial removal of colistin (43%-59% of total colistin clearance). Total colistin clearance was found to be reduced (varying between 3.3 and 4.5 L/h), compared with patients with normal renal function. Colistin methane sulphonate dosage resulted in clearly suboptimal colistin steady-state concentrations. CONCLUSIONS In spite of substantial extracorporeal clearance, total colistin clearance was reduced, compared with patients with normal renal function. Colistin adsorption by the haemofilter contributed to its extracorporeal clearance to a large extent. Studies on other patients receiving colistin methane sulphonate and undergoing CRRT are required before more appropriate dosage regimens can be recommended.

Role of New Biomarkers: Functional and Structural Damage

Traditional diagnosis of acute kidney injury (AKI) depends on detection of oliguria and rise of serum creatinine level, which is an unreliable and delayed marker of kidney damage. Delayed diagnosis of AKI in the critically ill patient is related to increased morbidity and mortality, prolonged length of stay, and cost escalation. The discovery of a reliable biomarker for early diagnosis of AKI would be very helpful in facilitating early intervention, evaluating the effectiveness of therapy, and eventually reducing cost and improving outcome. Innovative technologies such as genomics and proteomics have contributed to the discovery of new biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (Cys C), kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and liver-type fatty acid binding protein (L-FABP). The current status of the most promising of these novel AKI biomarkers, including NGAL, Cys C, KIM-1, L-FABP, and IL-18, is reviewed.

The effects of IgM-enriched immunoglobulin preparations in patients with severe sepsis: another point of view

We read with interest the paper by Tugrul et al. [1] regarding the effects of IgM-enriched immunoglobulin preparations in patients with severe sepsis managed in their intensive care unit. Apart from the global interest of reading a paper in the field of the treatment of severe sepsis and septic shock, we have an almost similar project in progress. It is well known that the immunotherapy in sepsis is still a gray zone, and it will remain so as long as the relevant literature presents conflicting results [2]. From our understanding and the interim analysis of our data, it seems that we could expect some definitive immunotherapy informationin the near future. In our study, we have presently included 34 patients in the treatment group (IgM + IgG + IgA) and 34 in the control group. Analyzing our data in a manner comparable with that of Tugrul et al. [1], we reach a different conclusion regarding the results. The only difference that exists between our protocol and that of Tugrul et al. regarding the study design and the inclusion criteria is that we include only adults older than 18 years old (the lower age limit of Tugrul et al.s study is 10 years, and adolescents are probably included). The number of patients needed per arm of the study in order to achieve a safe conclusion (statistical power analysis, 80%; P < 0.05 for a mortality decrease of 17%, which was the mortality decrease in our preliminary analysis) is 120 patients in each arm. In a study with a smaller number of patients, therefore, such as those of Tugrul et al. (21 patients in each arm) or ourselves (34 patients in each arm to the present time), any conclusion may be unsafe. Although the data in both studies (in our opinion) are so far not sufficient, a significant difference trend is recorded. The mean age in Tugrul et al.s study is 42.0 ± 18 years in the IgM + IgG + IgA group and 49.3 ± 20.6 years in the control group. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score in that same study is 10.5 ± 4.6 in the IgM + IgG + IgA group and 14.0 ± 8.5 in the control group. Although there is no statistically significant difference, there is a strong tendency for the two means to become different (P = 0.10). In our preliminary data analysis, the mean age is 50.5 ± 3.33 years in the IgM + IgG + IgA group and 50.7 ± 7.36 years in the control group. The APACHE II score in our study is 21.27 ± 7.23 in the IgM + IgG + IgA group and 23.5 ± 7.91 in the control group. The 28-day mortality rate in Tugrul et al.s study is 23.8% in the IgM + IgG + IgA group versus 33.3% in the control group. In our preliminary data analysis, the mortality rate is 22.35% and 40.0% in the IgM + IgG + IgA group and the control group, respectively. Although this difference is a statistically significant one, the analysis of the mortality rate of the subgroups according to the APACHE II scoring of inclusion to the study day is more interesting. The mortality rate in our preliminary data for the IgM + IgG + IgA group with an APACHE II score ranging between 20 and 29 was 22.22%, and that of the control group with the same APACHE II score range was 55%. As we pointed out earlier, in order to demonstrate the clinical effectiveness of immunotherapy in severe sepsis and septic shock, a number of 120 patients is necessary to be included in each arm of our study. Using our preliminary results in the same manner as those in Tugrul et al.s paper [1], we could conclude that it is sometimes possible to present the data in such a way resulting in delusive conclusions. Analyzing the data by means of definitions of sepsis and septic shock, and assuming the patients to be a uniform group, we cannot demonstrate the special subgroups of patients in whom the administration of IgM-enriched immunoglobulin preparations may have highly beneficial effects. By grouping the patients according to some characteristics (such as APACHE II score or Simplified Acute Physiology Score IIscore), the beneficial effect of immunoglobulins could be shown. Using such an approach, a beneficial effect of IgG immunotherapy in a special subgroup of septic patients has already been shown in the study by Dominioni et al. [3]. In conclusion, it seems that there is a subgroup of patients with severe sepsis or septic shock in which the delivery of IgM-enriched immunoglobulin preparations may have a beneficial effect. Further study with more patients, either in our study or that of Tugrul et al., is necessary before we decide whether to use this type of immunotherapy in the treatment of severe sepsis.

Mechanical ventilation and the immune response

We found no statistically significant increase (paired sample t test) in the supernatant of tracheal aspirates between baseline and 2 h after MV for tumor necrosis factor (TNF) α, interleukin (IL) 6, IL-10, TNF-RI and TNF-RII concentrations (Table 1, Fig. 1). TNF-α, TNF-RI, and TNF-RII concentrations in serum were also not significantly altered after 2 h of MV (Fig. 2). On the other hand, there was a statistically significant increase in mean serum concentrations of IL-6 and IL-10. However, examining individual data, only two patients undergoing abdominal surgery (colectomy and appendecectomy) showed a significant increase in these cytokines. Our findings do not confirm in general that MV can significantly alter immune response [1] either locally in the lungs or systematically in the circulation in adult patients without preexisting lung disease undergoing MV for elective surgery. However, there is evidence in two patients of systematic alterations in immune response, both proand anti-inflammatory, which can be attributed to surgical manipulations. Our findings do not confirm the findings either Intensive Care Med (2002) 28:1365–1366 DOI 10.1007/s00134-002-1425-0 C O R R E S P O N D E N C E

Daily interruption of central venous catheters in critically ill ICU patients

ICU patients require a central venous catheter (CVC) for solutions, and drug administration, transfusions of blood and blood products as well. The purpose of the study was to investigate the frequency of daily interruptions of CVC in critically ill patients. Catheter-related blood stream infections, especially due to Staphylococcus epidermidis, may be related to hand manipulation of the CVC during catheter interruptions.