Roberto Imberti

Steady-State Pharmacokinetics and BAL Concentration of Colistin in Critically Ill Patients After IV Colistin Methanesulfonate Administration

BACKGROUND Infections caused by multidrug-resistant gram-negative bacteria have caused a resurgence of interest in colistin. To date, information about pharmacokinetics of colistin is very limited in critically ill patients, and no attempts have been made to evaluate its concentration in BAL. METHODS In this prospective, open-label study, 13 adult patients with ventilator-associated pneumonia caused by gram-negative bacteria were treated with colistin methanesulfonate (CMS) IV, 2 million International Units (174 mg) q8h, a usually recommended dose, for at least 2 days. Blood samples were collected from each patient at time intervals after the end of infusion. BAL was performed at 2 h. Colistin was measured by a selective, sensitive high-performance liquid chromatography-based method. Pharmacokinetic parameters were determined by noncompartmental analysis. RESULTS Patients received 2.19 ± 0.38 mg/kg (range, 1.58-3.16) of CMS per dose. At steady state, mean ± SD plasma colistin maximum (Cmax) and trough (Ctrough) concentrations were 2.21 ± 1.08 and 1.03 ± 0.69 μg/mL, respectively. Mean ± SD area under the plasma concentration-time curve from 0 to 8 h (AUC(0-8)), apparent elimination half-life, and apparent volume of distribution were 11.5 ± 6.2 μg × h/mL, 5.9 ± 2.6 h, and 1.5 ± 1.1 L/kg, respectively. Cmax/minimum inhibitory concentration (MIC) ratio and AUC(0-24)/MIC ratio (MIC = 2 μg/mL) were 1.1 ± 0.5 and 17.3 ± 9.3, respectively. Colistin was undetectable in BAL. Nephrotoxicity was not observed. CONCLUSIONS Although the pharmacodynamic parameters that better predict the efficacy of colistin are not known in humans, in critically ill adult patients the IV administration of CMS 2 million International Units (174 mg) q8h results in apparently suboptimal plasma concentrations of colistin, which is undetectable in BAL. A better understanding of the pharmacokinetic-pharmacodynamic relationship of colistin is urgently needed to determine the optimal dosing regimen.

Pharmacokinetics of Colistin in Cerebrospinal Fluid after Intraventricular Administration of Colistin Methanesulfonate

ABSTRACT Intraventricular colistin, administered as colistin methanesulfonate (CMS), is the last resource for the treatment of central nervous system infections caused by panresistant Gram-negative bacteria. The doses and daily regimens vary considerably and are empirically chosen; the cerebrospinal fluid (CSF) pharmacokinetics of colistin after intraventricular administration of CMS has never been characterized. Nine patients (aged 18 to 73 years) were treated with intraventricular CMS (daily doses of 2.61 to 10.44 mg). Colistin concentrations were measured using a selective high-performance liquid chromatography (HPLC) assay. The population pharmacokinetics analysis was performed with the P-Pharm program. The pharmacokinetics of colistin could be best described by the one-compartment model. The estimated values (means ± standard deviations) of apparent CSF total clearance (CL/Fm, where Fm is the unknown fraction of CMS converted to colistin) and terminal half-life (t1/2λ) were 0.033 ± 0.014 liter/h and 7.8 ± 3.2 h, respectively, and the average time to the peak concentration was 3.7 ± 0.9 h. A positive correlation between CL/Fm and the amount of CSF drained (range 40 to 300 ml) was observed. When CMS was administered at doses of ≥5.22 mg/day, measured CSF concentrations of colistin were continuously above the MIC of 2 μg/ml, and measured values of trough concentration (Ctrough) ranged between 2.0 and 9.7 μg/ml. Microbiological cure was observed in 8/9 patients. Intraventricular administration of CMS at doses of ≥5.22 mg per day was appropriate in our patients, but since external CSF efflux is variable and can influence the clearance of colistin and its concentrations in CSF, the daily dose of 10 mg suggested by the Infectious Diseases Society of America may be more prudent.

Limbic hyperconnectivity in the vegetative state

Objective: To investigate functional connectivity between the default mode network (DMN) and other networks in disorders of consciousness. Methods: We analyzed MRI data from 11 patients in a vegetative state and 7 patients in a minimally conscious state along with age- and sex-matched healthy control subjects. MRI data analysis included nonlinear spatial normalization to compensate for disease-related anatomical distortions. We studied brain connectivity data from resting-state MRI temporal series, combining noninferential (independent component analysis) and inferential (seed-based general linear model) methods. Results: In DMN hypoconnectivity conditions, a patients DMN functional connectivity shifts and paradoxically increases in limbic structures, including the orbitofrontal cortex, insula, hypothalamus, and the ventral tegmental area. Conclusions: Concurrently with DMN hypoconnectivity, we report limbic hyperconnectivity in patients in vegetative and minimally conscious states. This hyperconnectivity may reflect the persistent engagement of residual neural activity in self-reinforcing neural loops, which, in turn, could disrupt normal patterns of connectivity.

Results of a prospective study (CATS) on the effects of thalamic stimulation in minimally conscious and vegetative state patients

OBJECTIVE Deep brain stimulation of the thalamus was introduced more than 40 years ago with the objective of improving the performance and attention of patients in a vegetative or minimally conscious state. Here, the authors report the results of the Cortical Activation by Thalamic Stimulation (CATS) study, a prospective multiinstitutional study on the effects of bilateral chronic stimulation of the anterior intralaminar thalamic nuclei and adjacent paralaminar regions in patients affected by a disorder of consciousness. METHODS The authors evaluated the clinical and radiological data of 29 patients in a vegetative state (unresponsive wakefulness syndrome) and 11 in a minimally conscious state that lasted for more than 6 months. Of these patients, 5 were selected for bilateral stereotactic implantation of deep brain stimulating electrodes into their thalamus. A definitive consensus for surgery was obtained for 3 of the selected patients. All 3 patients (2 in a vegetative state and 1 in a minimally conscious state) underwent implantation of bilateral thalamic electrodes and submitted to chronic stimulation for a minimum of 18 months and a maximum of 48 months. RESULTS In each case, there was an increase in desynchronization and the power spectrum of electroencephalograms, and improvement in the Coma Recovery Scale-Revised scores was found. Furthermore, the severity of limb spasticity and the number and severity of pathological movements were reduced. However, none of these patients returned to a fully conscious state. CONCLUSIONS Despite the limited number of patients studied, the authors confirmed that bilateral thalamic stimulation can improve the clinical status of patients affected by a disorder of consciousness, even though this stimulation did not induce persistent, clinically evident conscious behavior in the patients. Clinical trial registration no.: NCT01027572 ( ClinicalTrials.gov ).

1,2-Dichloropropane (DCP) toxicity is correlated with DCP-induced glutathione (GSH) depletion and is modulated by factors affecting intracellular GSH.

Acute 1,2-dichloropropane (DCP) poisoning in humans is relatively frequent in Italy, where DCP is widely diffused as a constituent of commercial solvents and dry cleaners. In this study we have investigated the effects of DCP on intracellular glutathione (GSH) content in main target tissues of male Wistar rats, i.e. liver, kidney and blood, in order to establish if a correlation between DCP-induced GSH depletion and tissue damage exists. Administration of DCP (2 ml/kg body weight orally) caused a dramatic loss of tissue GSH occurring 24 h after DCP intoxication, followed by a slow restoration approaching physiological levels after 96 h. GSH depletion was associated with a marked increase in serum GOT, GPT, 5′-nucleotidase, gamma-glutamyl transpeptidase, alkaline phosphatase, urea and creatinine, and a significant degree of hemolysis. When animals were pretreated with a GSH depleting agent, buthionine-sulfoximine (BSO) (0.5 g/kg body weight) i. p. 4 h before DCP intoxation, an increase of overall mortality was found, significantly different from the group of animals treated with DCP alone. On the contrary, the administration of a GSH precursor, N-acetylcysteine (NAC) i. p. (250 mg/kg body weight) 2 and 16 h after DCCP intoxication prevented the dramatic loss of cellular GSH and reduced the extent of injury in target tissues, as demonstrated by laboratory indices. Furthermore, statistical analysis of the data revealed a correlation between: (1) depletion of liver GSH and increase in serum GOT, GPT, 5′-nucleotidase, (2) depletion of kidney GSH and increase in serum urea and creatinine and (3) depletion of blood GSH and the occurence of hemolysis. Our findings demonstrate that GSH plays a critical role in modulating the toxicity of DCP. They also highlight the protective role of NAC and suggest that this glutathione precursor could rationally be employed in DCP poisoning in humans.

The importance of protecting the mechanical ventilator during colistin methanesulfonate nebulization

Dear Editor, We read with interest the paper by Athanassa and colleagues [1] on the pharmacokinetics of inhaled colistin methanesulfonate (CMS) in mechanically ventilated patients, demonstrating that aerosol administration allows one to achieve high drug concentrations in the epithelial lining fluid of the deep lung. The authors underline the importance of nebulization technology to optimize drug delivery to the lungs. Actually, the effective amount of drug reaching the airways can be increased from about 4 % up to 30 % of the emitted dose by selecting an optimal combination of respiratory circuit, nebulizer type, and position [2]. This also means that, whatever the method of nebulization, a substantial amount (70–96 %) of drug dose is lost within the ventilator circuit, possibly interfering with the function of sensors and/or valves. We report a case of sudden expiratory valve malfunction associated with CMS nebulization in a patient with multidrug-resistant Acinetobacter baumannii pneumonia. Pressuresupport ventilation was delivered by a Hamilton-G5 ventilator (Hamilton Medical, Bonaduz, Switzerland) through a heated circuit with active humidifier (RT340 Evaqua and MR850, Fisher&Paykel Healthcare, Auckland, New Zealand). CMS (UCB-Pharma, Turin, Italy; 1 M units in 5 ml) was administered 4 times/ day by a jet nebulizer (MallinckrodtDAR, Mirandola, Italy) placed between the inspiratory limb and Y-piece of the ventilator circuit. About 30 min after a nebulization session, an ‘‘exhalation obstructed’’ alarm message appeared, while a severe malfunction of the expiratory valve could be detected on the ventilator screen: at fulfillment of the criteria for cycling, the expiratory valve opened only after a hold lasting about 1 s (Fig. 1). By backward analysis we found that the problem had started as a slight opening delay just 5 min before critically worsening. The malfunction was resolved by the immediate replacement of the membrane and cover of the expiratory valve, thereafter protected with a DAR mechanical filter large (Covidien, Mansfield, USA). Expiratory filtering increased the expiratory resistance by 2 cmH2O/l/s, without further increase during the following 72 h of continuous use of the same filter. Our current policy in ventilated patients needing nebulization is to protect the expiratory valve with a mechanical filter that must be changed every 24 h or whenever signs of increased expiratory resistance appear. It should be emphasized that this solution seems effective and safe in our setting, with a specific combination of mechanical ventilator, circuit, humidifier, nebulizer type, and expiratory filter; different combinations might adversely affect the effectiveness or safety. Note that severe obstructions of the expiratory filters by aerosol particles (in one case complicated by cardiac arrest) have been reported during ceftazidime/ amikacin nebulization, despite filter removal after each aerosol administration as dictated by the study protocol [3]. In conclusion, clinicians must be aware that aerosol administration of CMS, or also other drugs, can lead to sudden and potentially dangerous malfunction of mechanical ventilators. Expiratory filtering may prevent this problem, but must be managed carefully because, in turn, it may be a source of dangerous obstruction. Automatic monitoring and alarming of expiratory resistance are important safety features of ventilators, but personnel should also be trained in detecting and correcting ventilator -1500 -1000 -500 0 50

Intraventricular or intrathecal colistin for the treatment of central nervous system infections caused by multidrug-resistant Gram-negative bacteria

Central nervous system infections caused by Gram-negative bacteria susceptible only to colistin are rare but life-threatening and increasing in prevalence. Given the current antibiotic development pipeline it is likely that the paucity of therapeutic options will continue for the next years. Colistin is an amphipathic bactericidal antibiotic which is administered systemically as colistin methanesulfonate (also known as colistimethate sodium). Colistin methanesulfonate is the inactive prodrug, and in cerebrospinal fluid undergoes spontaneous hydrolysis to colistin (the active form with antimicrobial activity). In this review, we describe and evaluate the clinical and experimental data supporting the use of intraventricular (IVT) or intrathecal (IT) colistin against multidrug-resistant Gram-negative infections of the central nervous system, describe the permeability of the blood-brain barrier to colistin, the pharmacokinetics of colistin after IVT administration of colistin methanesulfonate, its anti-endotoxin activity, discuss the opportunity to administer colistin intraventricularly or intrathecally and the dose regimen, and provide recommendations based on the available evidence.

Thyroxine pretreatment and halothane administration alter Ca2+ transport and transmembrane potential in rat liver mitochondria : an additional mechanism for halothane-induced liver damage in the hyperthyroid rat model

Male rats pretreated with thyroid hormones and exposed to halothane in non-hypoxic conditions develop acute liver damage. In order to investigate the mechanisms leading to liver damage in this animal model, the effects of thyroxine (T4) pretreatment and halothane administration on Ca2+ transport and transmembrane potential were studied in isolated rat liver mitochondria. Five-day T4-pretreatment reduced the mitochondrial Ca2+ loading capacity and increased the rate of Ca2+ cycling across the mitochondrial membrane. Halothane administration further increased Ca2+ cycling and produced a time- and dose-dependent loss of transmembrane potential which was more pronounced in mitochondria from T4-pretreated rats than in euthyroid animals. When mitochondria from T4-pretreated rats were incubated in the presence of the Ca2+ chelator EGTA, membrane potential was well preserved. In contrast, when Ca2+ concentration in the extramitochondrial medium was increased, mitochondria deenergization occurred earlier. These findings confirm that alterations in Ca2+ transport and mitochondrial function can be interrelated events and suggest that a Ca2+-dependent, halothane-induced loss of transmembrane potential could participate in generating acute liver damage in hyperthyroid rats exposed to halothane in non-hypoxic conditions.

Thyroid hormone therapy in organ donors

Sam Shemie and associates recommend that consideration be given to using thyroid hormone therapy in all organ donors.[1][1] We have experimental data suggesting that administering thyroid hormones to hemodynamically stable organ donors could decrease the success of liver transplants. In a model of