Sophia L. Markantonis

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.

Penetration of Colistin into Cerebrospinal Fluid

ABSTRACT Colistin penetration into the cerebrospinal fluid (CSF) was studied in five critically ill adult patients receiving colistin methanesulfonate for infections by multiresistant gram-negative bacilli. Colistin concentrations were determined in paired serum and CSF samples, with the latter taken by lumbar puncture, with the exception of one patient with an external ventriculostomy. CSF-to-serum ratios (0.051 to 0.057) for all study patients coincided at all sampling times. The low level (5%) of penetration suggests inadequate bactericidal colistin concentrations in the CSF.

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.

Oxidized LDL in human carotid plaques is related to symptomatic carotid disease and lesion instability

BACKGROUND Oxidative stress is an important determinant in atherosclerosis development. Various markers of oxidative stress, such as oxidation of low-density lipoprotein (LDL), nitrosative stress, lipid peroxidation, and protein oxidation, have been implicated in the initiation and/or progression of atherosclerosis, but their association with plaque erosion and symptomatic carotid disease has not been fully defined. In addition, certain oxidative markers have been shown in various models to promote plaque remodeling through matrix metalloproteinase (MMP) activation. OBJECTIVE To perform a global investigation of various oxidative stress markers and assess for potential relationships with destabilization and symptomatic development in human carotid plaques. METHODS Thirty-six patients undergoing endarterectomy were evaluated and compared with 20 control specimens obtained at the time of autopsy. Differences between stable and unstable plaques, symptomatic and asymptomatic patients, and >or=90% and <90% stenosis were evaluated. Oxidized LDL (ox-LDL), nitrotyrosine (NT), malondialdehyde (MDA), and protein carbonyls (PCs) levels were determined in atheromatic plaques homogenates by corresponding biochemical assays. Immunohistochemical (IHC) analysis was also employed to determine the percentage and topological distribution of cells expressing NT and metalloproteinase-9 (MMP-9) in serial sections from corresponding atheromatic plaques. MMP-9 expression was further verified using Western blot analysis. RESULTS Ox-LDL was increased in symptomatic patients (P < .05). Also, ox-LDL and NT levels were significantly higher in unstable versus stable carotid plaques (P < .05, respectively). Furthermore, IHC serial section analysis, corroborated by statistical analysis, showed a topological and expressional correlation between NT and MMP-9 (P < .05). MDA and PCs levels, although increased in carotid plaques, did not distinguish stable from unstable carotid plaques as well as symptomatic from asymptomatic patients with various degrees of stenosis. CONCLUSION All types of investigated oxidative stress markers were significantly increased in human carotid plaques, but only ox-LDL levels were associated with clinical symptoms, while peroxynitrite products and MMP-9 were specifically related to plaque instability.

Combined Intravenous and Intraventricular Administration of Colistin Methanesulfonate in Critically Ill Patients with Central Nervous System Infection

ABSTRACT Colistin pharmacokinetics were prospectively studied after intravenous administration of colistin methanesulphonate in critically ill patients without central nervous system infection (controls, n = 5) and in patients with external ventricular drain-associated ventriculitis after intravenous administration (EVDViv, n = 3) or combined intravenous/intraventricular administration (EVDVcomb, n = 4). Cerebrospinal fluid (CSF)/serum colistin concentration ratios were higher in EVDViv than in control patients (11% versus 7%, P ≤ 0.05) and in EVDVcomb compared to all other patients (P < 0.0001). CSF colistin concentrations above the MIC of 0.5 μg/ml were achieved only in EVDVcomb patients.

Relationships Between the Concentrations of Prostaglandins and the Nonsteroidal Antiinflammatory Drugs Indomethacin, Diclofenac, and Ibuprofen

Study Objectives. To study the concentration‐effect relationships of the nonsteroidal antiinflammatory drugs (NSAIDs) indomethacin, diclofenac, and ibuprofen; to investigate whether standard doses of these drugs inhibit prostaglandin concentrations to a similar extent, determined by measuring the concentration of a surrogate marker of prostaglandin E2 (PGE2); and to determine the extent to which dose increases produce analogous increases in prostaglandin inhibition.

Effects of Darbepoetin Alfa on Plasma Mediators of Oxidative and Nitrosative Stress in Anemic Patients With Chronic Heart Failure Secondary to Ischemic or Idiopathic Dilated Cardiomyopathy

Increased oxidative and nitrosative stress are important mediators of left ventricular (LV) and vascular dysfunction in patients with chronic heart failure (CHF). This study investigated the effects of darbepoetin alfa on plasma markers of oxidative and nitrosative stress in patients with CHF with anemia. Thirty patients with CHF (LV ejection fraction [LVEF] <40%, hemoglobin <12.5 g/dl, and serum creatinine <2.5 mg/dl) were randomly assigned (1:1) to receive either a 3-month darbepoetin alfa regimen at 1.5 microg/kg every 20 days plus oral iron or placebo plus oral iron. Plasma B-type natriuretic peptide (BNP), markers of oxidative (oxidative, malondialdehyde, carbonyl proteins; antioxidative, glutathione) and nitrosative (nitrotyrosine) stress, LVEF, and 6-minute walked distance were assessed at baseline and after treatment. A significant improvement in LVEF and 6-minute walked distance was observed in only darbepoetin-treated patients. Plasma BNP (F = 14.8, p = 001), malondialdehyde (F = 9.4, p = 0.006), protein carbonyl (F = 9.2, p = 0.006), and nitrotyrosine (F = 4.4, p = 0.045) were significantly decreased, along with an increase in antioxidative glutathione (F = 4.2, p = 0.049) after darbepoetin alfa treatment. These factors were unaffected in placebo-treated patients. Darbepoetin-induced percentages of change in carbonyl protein significantly correlated with respective changes in plasma BNP (r = 0.55, p <0.05) and LVEF (r = -0.46, p <0.05). Finally, a drug-induced percentage of decrease in nitrotyrosine significantly correlated with the respective improvement in 6-minute walked distance (r = -0.63, p <0.05). In conclusion, darbepoetin alfa attenuated deleterious effects of oxidative and nitrosative stress into the cardiovascular system of anemic patients with CHF, improving also cardiac function and exercise capacity.

Acupressure on the Extra 1 Acupoint: The Effect on Bispectral Index, Serum Melatonin, Plasma β-endorphin, and Stress

BACKGROUND: Acupressure on the “extra 1” point decreases bispectral index (BIS) values and stress. METHODS: We investigated the BIS, melatonin, β-endorphin, and verbal stress score values before, after 10 min of acupressure application on the extra 1 point, on a sham point, after no acupressure, and 1 h after completion of each intervention in 12 volunteers. RESULTS: The BIS and verbal stress score values were decreased after acupressure on the extra 1 point (P = 0.0001 and P = 0.008, respectively), but melatonin and β-endorphin did not change. CONCLUSION: Acupressure on the extra 1 point has no effect on melatonin and β-endorphin levels.

Caffeine versus theophylline for apnea of prematurity: a randomised controlled trial.

Aim:  To compare standard doses of theophylline and caffeine for apnea of prematurity in terms of apnea frequency and assess the need for therapeutic drug monitoring.

Effects of blood loss and fluid volume replacement on serum and tissue gentamicin concentrations during colorectal surgery

BACKGROUND The prophylactic administration of antimicrobial agents to surgical patients has become standard practice to minimize the risk for postsurgical infection. During surgery, factors such as renal clearance, fluid administration, and blood loss contribute to drug concentrations achieved in the blood and tissues. The aminoglycoside gentamicin was chosen to investigate these factors because it is used for standard antimicrobial prophylaxis in colorectal surgery. OBJECTIVE The aim of this study was to investigate the effects of surgical blood loss and fluid volume replacement on gentamicin concentrations in serum and in 3 tissue types (subcutaneous fat, epiploic fat, and colonic wall) in patients undergoing colorectal surgery. METHODS This uncontrolled, open-label study was conducted at the Aretaieion Hospital (Athens, Greece) between November 2002 and March 2003. Patients selected for this study were scheduled to undergo elective colorectal surgery of ? 2-hour duration with general and epidural anesthesia and to receive gentamicin as major antimicrobial prophylaxis. Blood and tissue samples were obtained concurrently at specific times throughout each procedure. The effect of intraoperative blood loss on gentamicin concentrations and its pharmacokinetic properties was determined. RESULTS Sixteen patients completed the study (11 men, 5 women; white race, 16 patients [100%]; mean [SD] age, 61 [3] years [range, 39-80 years]). Mean (SEM) serum gentamicin concentration was found to be insufficient; the maximum plasma drug concentration/minimum inhibitory concentration (MIC) ratio was <8:1 for pathogens commonly isolated in the surgical unit of the hospital (MIC: 1-4 microg/mL). The mean (SEM) concentration at first surgical incision was 7.83 (0.82) microg/mL and decreased to 2.60 (0.28) microg/mL at skin closure, resulting in borderline effectiveness even for susceptible gram-positive microorganisms (MIC approximately 1.0). Initially, mean (SEM) tissue gentamicin concentrations in subcutaneous fat, epiploic fat, and colonic wall were low (2.02 [0.34] microg/mL, 2.41 [0.42] microg/mL, and 1.93 [0.38] microg/mL, respectively) and decreased approximately 1.0 microg/mL ( approximately 50%) by skin closure. Statistically significant positive correlations were found between gentamicin concentrations in serum and tissues (P </= 0.03). A strong negative correlation was found between the intravenously administered fluids and gentamicin concentrations in serum and tissues (P </= 0.04). CONCLUSIONS In this study, the administration of a 2-mg/kg dose of gentamicin as antimicrobial prophylaxis during colorectal surgery associated with significant intraoperative blood loss and therefore requiring significant fluid replacement did not achieve concentrations of the drug above MICs for gram-negative microorganisms throughout the procedures in either serum or tissue samples.