Colistin: recent data on pharmacodynamics properties and clinical efficacy in critically ill patients

Recent clinical studies performed in a large number of patients showed that colistin "forgotten" for several decades revived for the management of infections due to multidrug-resistant (MDR) Gram-negative bacteria (GNB) and had acceptable effectiveness and considerably less toxicity than that reported in older publications. Colistin is a rapidly bactericidal antimicrobial agent that possesses a significant postantibiotic effect against MDR Gram-negative pathogens, such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. The optimal colistin dosing regimen against MDR GNB is still unknown in the intensive care unit (ICU) setting. A better understanding of the pharmacokinetic-pharmacodynamic relationship of colistin is urgently needed to determine the optimal dosing regimen. Although pharmacokinetic and pharmacodynamic data in ICU patients are scarce, recent evidence shows that the pharmacokinetics/pharmacodynamics of colistimethate sodium and colistin in critically ill patients differ from those previously found in other groups, such as cystic fibrosis patients. The AUC:MIC ratio has been found to be the parameter best associated with colistin efficacy. To maximize the AUC:MIC ratio, higher doses of colistimethate sodium and alterations in the dosing intervals may be warranted in the ICU setting. In addition, the development of colistin resistance has been linked to inadequate colistin dosing. This enforces the importance of colistin dose optimization in critically ill patients. Although higher colistin doses seem to be beneficial, the lack of colistin pharmacokinetic-pharmacodynamic data results in difficulty for the optimization of daily colistin dose. In conclusion, although colistin seems to be a very reliable alternative for the management of life-threatening nosocomial infections due to MDR GNB, it should be emphasized that there is a lack of guidelines regarding the ideal management of these infections and the appropriate colistin doses in critically ill patients with and without multiple organ failure

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 E-2 (PGE(2)); and to determine the extent to which dose increases produce analogous increases in prostaglandin inhibition. Design. Single-dose, randomized, crossover trial with a 1-week washout period. Setting. University biopharmaceutics and pharmacokinetics laboratory. Subjects. Eight healthy adult volunteers younger than 35 years old. Intervention. Subjects were administered two different standard doses of regular formulations (not enteric coated) of each NSAID on separate occasions. Measurements and Main Results. Plasma samples were collected for determination of drug and 13,14-dihydro-15-keto-PGE(2) (PGEM; the surrogate marker of PGE(2)) concentrations at regular intervals after administration of each NSAID dose. Statistically significant linear correlations were found between the percent reduction in PGEM concentration and the concentrations of diclofenac, indomethacin, and ibuprofen 2 in Plasma (R-2 = 0.992-0.999). The PGEM plasma concentrations correlated inversely with NSAID plasma concentrations, indicating maximum inhibition when the highest NSAID plasma concentrations were achieved. Statistically significant differences in the percent inhibition of PGEM concentrations were observed between the two doses for each NSAID (p<0.05), but not between subjects for each NSAID. Doubling the dose (100% increase) of diclofenac and indomethacin produced a 60-65% increase in maximum inhibition of PGEM concentrations, whereas a 50% increase in dose produced a 44% increase in the maximum effect of ibuprofen. Conclusion. Prostaglandin inhibition, as measured by changes in PGEM concentrations, correlated significantly with NSAID concentrations in plasma and differed significantly between high and low NSAID doses. Measurement of PGEM plasma concentrations appears to be a promising marker for estimation of relative potency of NSAIDs. Conclusion. Prostaglandin inhibition, as measured by changes in PGEM concentrations, correlated significantly with NSAID concentrations in plasma and differed significantly between high and low NSAID doses. Measurement of PGEM plasma concentrations appears to be a promising marker for estimation of relative potency of NSAIDs

Evidence of tachyphylaxis associated with salmeterol treatment of chronic obstructive pulmonary disease patients

Bronchodilator therapy is lifelong mandatory for chronic obstructive pulmonary disease patients. There is evidence of loss of bronchodilator effectiveness over time with beta(2)-agonists but not with anticholinergics. The aim of this study was to examine the development of tachyphylaxis to the long-acting beta(2)-agonist salmeterol using as a control therapeutic regimen the combination of ipratropium bromide and salbutamol sulphate. Fifty-six subjects participated in a 20-week, crossover randomised clinical trial. The parameters forced expiratory volume at 1 s (FEV1), peak expiratory flow rate (PEFR) and FEV1/forced vital capacity were measured via spirometry and the parameters Delta FEV1%pre, Delta PEFR%pre and Delta AUC(0-2) h were calculated. FEV1 increased significantly after two weeks of treatment with the combination treatment but not with the salmeterol. The observed diminished increase could be attributed to the development of tolerance to the long acting beta(2)-agonist. Salmeterol seems to be an effective bronchodilator, however, its duration of action over time and its peak effect might be subject to tachyphylaxis

Monitoring of subcutaneous dalteparin in patients with renat insufficiency under intensive care: an observational study

Objective: The objective of this study was to investigate the pharmacodynamic parameters of dalteparin in patients with renal insufficiency under intensive care. Materials and Methods: In this open, nonrandomized, nonblinded, prospective, single-dose observational study, 10 critically ill patients with renal insufficiency (mean creatinine clearance 29.5 +/- 6.42 mL/mm) were administered a single 5000-IU Subcutaneous dose of dalteparin. Results: Dalteparin blood levels were estimated indirectly over a 12-hour period by measuring anti-Xa activity and by performing a clotting assay known as the ATHU (AHEPA Thrombosis and Hemostasis Unit) test. Maximum anti-Xa activity (ie, 0.42 +/- 0.13 IU/mL) was achieved 4 hours after administration (in 8 of 10 patients). Adequate anticoagulant activity was maintained throughout the 12-hour dosage interval in all study patients. However, at time 0 hour of the study, 36 hours after the administration of a previous dose of dalteparin, considerable anti-Xa activity (ie, 0.39 +/- 0.11 IU/mL) was measured in 6 patients. A good correlation was found between anti-Xa activity and the results of the ATHU test. Conclusions: The presence of medium/severe edema and the concurrent administration of 1 to 3 inotropic drugs appear to contribute to a decrease in the rate of elimination of dalteparin, resulting in a greater-than-expected (as a result of decreased renal function) prolongation of its pharmacologic activity. We recommend that care be taken with repeated dosing of dalteparin in intensive care unit patients taking inotropic drugs until observed results can be confirmed. (c) 2006 Elsevier Inc. All rights reserved

A study of the effect of theophylline on the anti-inflammatory potency of dexamethasone using alpha-aminoisobutyric acid uptake in rat skin fibroblasts: A possible mechanism through the glucocorticoid receptor

The action of theophylline on the uptake of a-aminoisobutyric acid (AIB; an indicator of anti-inflammatory potency) stimulated by the glucocorticoid, dexamethasone, in cultured rat fibroblast monolayers was evaluated. Theophylline alone (0.1 mM) did not show significant activity (3314 +/- 27 cpm) compared with the baseline level (3186 +/- 130 cpm), but in the presence of 10 nM dexamethasone the stimulation of AIB uptake was increased to 5263 +/- 100 cpm, approximately to the same extent as with 100 nM dexamethasone alone (5397 +/- 28 cpm); Activation of glucocorticoid-receptor complexes in rat fibroblast cytosol was studied by assessing the extent of their binding to DNA-cellulose. Activated and non-activated forms of glucocorticoid-receptor complexes were analysed by DEAE-Sephadex chromatography. Theophylline (1 mM) was found to have a direct effect (0 degrees C), similar to that of heat (25 degrees C) on DNA-celulose binding, that is approximately 64.5% and 68.7%, respectively, thus indicating that theophylline promotes activation of glucocorticoid receptors at low temperature. The effect of theophylline on the stimulation of AIB uptake by dexamethasone when considered in the light of its activation of GR receptors in the fibroblast cytosol indicates that this effect may be mediated by GR activation. (O) 1998 Academic Press

Recovery and cognitive function after fentanyl or remifentanil administration for carotid endarterectomy

Study Objective: To compare recovery and restoration of cognitive function after fentanyl-propofol or remifentanil-propofol anesthesia administration in patients undergoing carotid endarterectomy. Design: Randomized, double-blind, prospective study. Setting: Department of Anesthesiology, University hospital. Patients: Seventy patients with ASA physical statuses II and III (53 men and 17 women) undergoing elective carotid endarterectomy. Interventions: Anesthetic technique and drugs were identical in the 2 groups, with the exception of remifentanil and fentanyl administration. Induction of anesthesia was obtained with a bolus dose of propofol (1-2 mg/kg), maintenance was achieved with a propofol infusion according to hemodynamics and nitrous oxide/oxygen (FIO2, 0.50). Muscle relaxation was achieved with rocuronium. The remifentanil group received I mu g/kg of remifentanil as a single dose during the-induction of anesthesia and 0.5 mu g/kg per minute as an infusion throughout the procedure. The fentanyl group received 2 mu g/kg of fentanyl as a single dose during the induction of anesthesia. Measurements: Intraoperative hemodynamic adverse events were recorded. All patients were also evaluated with regard to their recovery and the restoration of their cognitive function, recording the immediate recovery times and using the Aldrete score 15 and 60 minutes after surgery and the Hasegawa scale 6 hours after surgery. For evaluation of postoperative pain, the Numeric Pain Scale (0-10) was used. Main Results: Patients receiving remifentanil had significantly (P <.05) fewer episodes of intraoperative hypertension and needed nitroglycerine administration less frequently (P <.05) than those receiving fentanyl. Immediate recovery was significantly earlier (P <.05) with remifentanil (eye opening, 5.1 +/- 1.3 [remifentanil] and 7.2 +/- 3.7 [fentanyl] minutes; extubation time, 5.4 +/- 1.9 [remifentanil] and 7.8 +/- 4.1 [fentanyl] minutes). The Hasegawa Dementia Scale scores 6 hours after surgery and Aldrete scores 15 and 60 minutes after surgery did not differ significantly between the 2 groups. Pain levels were also similar for patients taking remifentanil and fentanyl. Conclusions: Although intraoperative hemodynamics were better preserved and immediate recovery was more rapid with remifentanil, overall postoperative recovery and restoration of cognitive functions as well as postoperative pain intensity seem to be similar for patients receiving remifentanil and for those receiving fentanyl combined with propofol for carotid endarterectomy operations. (c) 2005 Elsevier Inc. All rights reserved

Penetration of gentamicin into the alveolar lining fluid of critically ill patients with ventilator-associated pneumonia

Study objectives: To estimate the penetration of gentamicin into lung tissue by measuring its concentrations in alveolar lining fluid (ALF) and blood in critically ill patients with ventilator-associated pneumonia (VAP). Patients and interventions: The study population consisted of 24 patients who were admitted to an ICU for respiratory failure and developed VAP. Patients were scheduled to undergo bronchoscopy with BAL after IV administration of a once-daily, 240-mg schedule of gentamicin for the treatment of VAP. Patients were assigned at random to one of four groups of six patients each according to the scheduled time for bronchoscopy (1, 2, 4, or 6 h, respectively). A serum sample was obtained at 0.5 h (n = 24), and both serum and ALF samples (n = 6) were collected at each of the above specified times for measurement of antibiotic concentrations. Measurements and results: Mean +/- SEM gentamicin concentrations in the AILF were 2.95 +/- 0.37, 4.24 +/- 0.42, 3.10 +/- 0.39, and 2.65 +/- 0.35 mu g/mL at 1, 2, 4, and 6 h, respectively, after the start of antibiotic infusion. Maximum gentamicin concentrations in serum (13.39 +/- 0.91 mu g/mL, n = 24) and ALF (4.24 0.42 mu g/mL, n = 6) were achieved at 0.5 h and 2 h, respectively, giving a penetration ratio of 0.32. The mean ratios of ALF/serum concentrations between 1 h and 6 h ranged from 0.30 to 1.14. After completion of the distribution phase, a significant positive correlation (p = 0.02) was found between gentamicin concentrations in the serum and ALF. Conclusions: Once-daily IV administration of 240-mg gentamicin achieved average peak antibiotic concentrations of 4.24 mu g/mL in the ALF 2 h after administration, and an ALF/serum penetration ratio of 32%. Higher gentamicin doses to produce higher peak blood levels than those found with the study dose are necessary to obtain active alveolar concentrations against less sensitive microorganisms in the treatment of VAP in ICU patients