Search PubMed⌕ Search

Biomedical subjects

Mervyn Singer

Publications and source records attributed to Mervyn Singer.

At least 37 records · Page 2Linked to original sources
PubMed2005

Pharmacokinetic studies of linezolid and teicoplanin in the critically ill.

OBJECTIVES: To determine the pharmacokinetic characteristics of linezolid and teicoplanin in critically ill patients. PATIENTS AND METHODS: Serum was collected frequently during day 0 and then pre- and 1 h post-dose on days 1, 2, 3, 5, 7 and every third day thereafter during treatment. Serum linezolid concentrations were analysed using HPLC. Serum teicoplanin levels were analysed by fluorescence polarization immunoassay. RESULTS: A two-compartment model was required to characterize linezolid pharmacokinetics (n=28) and account for the accumulation seen after multiple dosing. The estimated clearance was 0.049 +/-0.016 L/h/kg (+/-s.e.m. of estimate). At steady state (dosing interval 12 h), linezolid serum concentrations exceeded the breakpoint of 4 mg/L for 10.88 h (95% CI 10.09-11.66) after a 600 mg dose with an AUC/MIC of 92.4 (95% CI 57.2-127.7). Teicoplanin was best described by a two-compartment model (n=26). The clearance was 4.97+/-1.58 L/h. Serum levels exceeded the breakpoint of 4 mg/L for the entire dosing interval in all subjects (400 mg dose every 12 h) with an AUC/MIC of 399.3 (95% CI 329.6-469.0). However, only four of 14 exceeded trough serum concentrations of 10 mg/L. For both agents, trough levels were similar in those who survived and those who died. CONCLUSIONS: Linezolid dosage at 600 mg every 12 h was adequate in the critically ill without need for adjustment for renal function. For teicoplanin, further study is needed to confirm if a trough of 10 mg/L is associated with a higher rate of cure than 5 mg/L. If so, serum drug assays would be needed to ensure a therapeutic level.

Acetamides↗
PubMed2005

Nitrosyl heme production compared in endotoxemic and hemorrhagic shock.

We compared nitric oxide production and nitrosyl hemoglobin steady state concentrations during the early phases of endotoxemic and hemorrhagic shock of equivalent severity. Sprague-Dawley rats were randomly assigned to (1) sham-operated control, (2) hemorrhage, and (3) intravenous endotoxin. Electron paramagnetic resonance spectroscopy was used to measure NO in the vasculature (binding to hemoglobin) and in the liver (binding to cytochrome P450). Despite similar changes in cardiorespiratory variables and identical microvascular pO(2), nitrosyl hemoglobin concentrations were significantly higher in endotoxemic rats than in rats in hemorrhagic shock, suggesting increased rates of NO production. A substantial venous minus arterial concentration gradient was observed for nitrosyl hemoglobin. This increased in line with the plasma total nitrite + nitrate concentration. Nitrosyl hemoglobin formation is likely to occur predominantly in the venous pool, suggesting that removal of NO from hemoglobin in the presence of oxygen may be faster than previously thought. In the liver, an increase in intracellular heme-NO complexes was detected in endotoxemic rats compared with rats in hemorrhagic shock; this was associated with increased reduction of the mitochondrial respiratory chain and is suggestive of NO inhibition of mitochondrial respiration.

Animals↗
PubMed2005

The pore-forming subunit of the K(ATP) channel is an important molecular target for LPS-induced vascular hyporeactivity in vitro.

ATP-sensitive K(+) (K(ATP)) channel activation is implicated in the vascular hyporeactivity occurring in septic shock. However, channel inhibition with the sulphonylurea receptor (SUR) antagonist, glibenclamide (Glib) fails to reverse lipopolysaccharide (LPS)-induced vascular hyporeactivity in vitro. We investigated whether inhibitors that act by binding to the K(ATP) channel pore could be effective. Ring segments of endothelium-intact rat mesenteric artery were incubated with LPS in culture media for either 6 or 20 h before contractile responses to phenylephrine were assessed in the absence or presence of K(ATP) channel inhibitors. The pore-forming subunit inhibitors barium chloride (BaCl(2); 300 microM) and PNU-37883A (1 microM) significantly reversed hyporeactivity at both time points, although less so at 20 h. In contrast, the SUR inhibitors, Glib (10 microM), tolbutamide (Tolb) (1 mM) and PNU-99963 (1 microM) were ineffective. In LPS-incubated tissues, Glib and Tolb antagonised contractions to the thromboxane A2 mimetic, U46619 (9,11-dideoxy-9alpha, 11alpha-methanoepoxy prostaglandin F(2alpha)) (10(-7) M), whereas the pinacidil-derived inhibitor, PNU-99963, did not. Contractions to 60 mM KCl were unaffected by LPS at 6 h, but were significantly depressed by LPS at 20 h, suggesting that K(+)-channel-independent pathways contribute to hyporeactivity at the later time point. The inducible nitric oxide synthase (iNOS) inhibitor, 1400 W (10 microM) and Tolb inhibited the production of nitrite induced by LPS, whereas BaCl(2) and PNU-37883A had no effect. In conclusion, K(ATP) channels contribute to LPS-induced vascular hyporeactivity via the iNOS pathway in rat mesenteric artery. The effectiveness of pore inhibitors over SUR inhibitors of the K(ATP) channel suggests altered SUR function following LPS administration, which cannot be explained by thromboxane receptor inhibition.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2004

Hypoxia accelerates nitric oxide-dependent inhibition of mitochondrial complex I in activated macrophages.

Excess production of nitric oxide (NO) is implicated in the development of multiple organ failure, with a putative mechanism involving direct mitochondrial inhibition, predominantly affecting complex I. The persistent effects of NO on complex I may be mediated through S-nitrosylation and/or nitration. The temporal contribution of these chemical modifications to the inhibition of respiration and the influence of concurrent hypoxia have not been previously examined. We therefore addressed these questions using J774 macrophages activated by endotoxin and interferon-gamma over a 24-h period, incubated at 21% and 1% oxygen. Oxygen consumption and complex I activity fell progressively over time in the activated cells. This was largely prevented by coincubation with the nonspecific NO synthase inhibitor L-N5-(1-iminoethyl)-ornithine. Addition of glutathione ethyl ester reversed the inhibition at initial time points, suggesting an early mechanism involving nitrosylation. Thereafter, the inhibition of complex I became more persistent, coinciding with a progressive increase in mitochondrial nitration. Hypoxia accelerated the persistent inhibition of complex I, despite a reduction in the total amount of NO generated. Our results suggest that hypoxia amplified the mitochondrial inhibition induced by NO generated during inflammatory disease states.

Animals↗
PubMed2004

Prospective audit of bacteraemia management in a university hospital ICU using a general strategy of short-course monotherapy.

OBJECTIVE: As optimal antibiotic therapy for bacteraemia remains unknown, different strategies have evolved. Routine practice in the University College London Hospitals intensive care unit (ICU) is to use short-course (5-6 days) monotherapy, unless specifically indicated (e.g. endocarditis, osteomyelitis). We decided to assess this approach for treating community-, hospital-, and ICU-acquired bacteraemia by monitoring clinical response, relapse rate and patient outcome. DESIGN: Six-month prospective observational study from February to July 2000. SETTING: Mixed medical-surgical tertiary referral ICU. PATIENTS: All 713 patients admitted to the ICU over the study period. MEASUREMENTS AND RESULTS: In total, 102 bacteraemic episodes occurred in 84 patients. Eight (57%) of 14 community-acquired bacteraemias, 22 (79%) of 28 hospital-acquired bacteraemias, and 48 (80%) of 60 ICU-acquired bacteraemias (in 49 patients) were treated with short-course monotherapy. Compared with previous reported studies, these patients had a low rate (23.8%) of death directly attributable to the bacteraemia and a satisfactory clinical response in 72%. Of six relapses (all Gram-negative), four had received combination therapy for severe deep-seated infections. ICU-acquired multidrug-resistant Gram-negative bacteraemias (6.5%) and fungaemias (3%) were also uncommon. No patient discharged from ICU subsequently developed a new bacteraemia relapse, or any long-term complication such as osteomyelitis. CONCLUSIONS: Our general strategy of short-course antibiotic monotherapy for treating bacteraemia in the critically ill appears to provide a satisfactory clinical response, low relapse rate and no long-term complications in a well-defined group of patients. Multicentre studies are warranted to compare short versus long course therapy, and monotherapy versus combination therapy.

Anti-Bacterial Agents↗
PubMed2004

The validity of trans-esophageal Doppler ultrasonography as a measure of cardiac output in critically ill adults.

OBJECTIVE: To determine the validity of the esophageal Doppler monitor (EDM) and echo-esophageal Doppler (Echo-ED) in measuring cardiac output in the critically ill. DESIGN: Systematic search of relevant international literature and data synthesis. SEARCH STRATEGY: Literature search (1989-2003) using Ovid interface to Medline, Embase and Cochrane databases aimed at finding studies comparing EDM or Echo-ED cardiac output with that derived from simultaneous pulmonary artery thermodilution (PAC(TD)) with Bland Altman measures of validity. PATIENTS: Critically ill adults in operating departments or intensive care units. DATA SYNTHESIS: Summary validity measures synthesized from Bland Altman analyses included pooled median bias and the median percentage of clinical agreement (PCA) derived from the limits of agreement. MAIN RESULTS: Eleven validation papers for EDM (21 studies) involving 314 patients and 2,400 paired measurements. The pooled median bias for PAC(TD) versus EDM was 0.19 l/min (range -0.69 to 2.00 l/min) for cardiac output (16 studies), and 0.6% (range 0-2.3%) for changes in cardiac output (5 studies). The pooled median percentage of clinical agreement for PAC(TD) versus EDM was 52% (interquartile range 42-69%) for cardiac output and 86% (interquartile range 55-93%) for changes in cardiac output. These differences in PCA were significant ( p=0.03 Mann-Whitney) for bolus PAC(TD) as the clinical "gold standard". We found an insufficient number of studies (2 papers) to assess the validity of Echo-ED. CONCLUSIONS: The esophageal Doppler monitor has high validity (no bias and high clinical agreement with pulmonary artery thermodilution) for monitoring changes in cardiac output.

Adult↗
PubMed2004

Randomised controlled trial assessing the impact of a nurse delivered, flow monitored protocol for optimisation of circulatory status after cardiac surgery.

OBJECTIVE: To assess whether a nurse led, flow monitored protocol for optimising circulatory status in patients after cardiac surgery reduces complications and shortens stay in intensive care and hospital. DESIGN: Randomised controlled trial. SETTING: Intensive care unit and cardiothoracic unit of a university teaching hospital. PARTICIPANTS: 174 patients who underwent cardiac surgery between April 2000 and January 2003. INTERVENTIONS: Patients were allocated to conventional haemodynamic management or to an algorithm guided by oesophageal Doppler flowmetry to maintain a stroke index above 35 ml/m2. RESULTS: 26 control patients had postoperative complications (two deaths) compared with 17 (four deaths) protocol patients (P = 0.08). Duration of hospital stay in the protocol group was significantly reduced from a median of nine (interquartile range 7-12) days to seven (7-10) days (P = 0.02). The mean duration of hospital stay was reduced from 13.9 to 11.4 days, a saving in hospital bed days of 18% (95% confidence interval -12% to 47%). Usage of intensive care beds was reduced by 23% (-8% to 59%). CONCLUSION: A nurse delivered protocol for optimising circulatory status in the early postoperative period after cardiac surgery may significantly shorten hospital stay.

Aged↗
PubMed2004

Linezolid versus teicoplanin in the treatment of Gram-positive infections in the critically ill: a randomized, double-blind, multicentre study.

OBJECTIVES: Linezolid, the only commercially available oxazolidinone, is indicated for the treatment of Gram-positive infections, although little has been published specifically on its use in the critically ill. A randomized, prospective study was therefore performed to compare linezolid with the glycopeptide antibiotic, teicoplanin, for the treatment of suspected or proven Gram-positive infections in an intensive care population. METHODS: Using a double-blind, double-dummy, prospective design, patients were randomized to (i) intravenous linezolid (600 mg/12 h) plus teicoplanin dummy [one dose/12 h for three doses then every 24 h intravenously (iv)] or (ii) teicoplanin (400 mg/12 h for three doses then 400 mg/24 h iv) plus linezolid dummy (one dose/12 h iv). Other antibiotics were used in combination with the trial agents in empirical treatment. Clinical and microbiological assessments were made daily in the first week, and at 8 and 21 days after treatment. RESULTS: One hundred patients received linezolid plus placebo-teicoplanin, whereas 102 received teicoplanin plus placebo-linezolid. Population baseline characteristics were similar in both groups. At end of treatment, clinical success [71 (78.9%) linezolid versus 67 (72.8%) teicoplanin] and microbiological success [49 (70.0%) versus 45 (66.2%)] rates were similar, as were adverse effects, intensive care unit mortality, and success rates at short- and long-term follow-up. Linezolid was superior at initial clearance of methicillin-resistant Staphylococcus aureus (MRSA) colonization (end of treatment, 51.1% versus 18.6%, P = 0.002). Two MRSA isolates showed reduced susceptibility to teicoplanin. CONCLUSIONS: Linezolid has similar safety and efficacy to teicoplanin in treating Gram-positive infections in the critically ill. Short-term MRSA clearance achieved with linezolid suggests better skin and mucosal penetration.

Acetamides↗
PubMed2004

Human septic myopathy: induction of cyclooxygenase, heme oxygenase and activation of the ubiquitin proteolytic pathway.

BACKGROUND: Skeletal muscle failure and wasting are manifestations of sepsis in humans that leads to serious and prolonged complications. The authors investigated the role of the major proinflammatory and antiinflammatory pathways, namely the inducible isoforms cyclooxygenase (COX-2) and heme oxygenase (HO-1), and the ubiquitin proteolytic pathway in skeletal muscle of septic patients. METHODS: Protein expression was detected by Western blot techniques. Muscle biopsies were taken from two muscle groups, rectus abdominis and vastus lateralis, of septic and control patients. RESULTS: The study showed an increase in COX-2 and HO-1 proteins expression and an activation of the proteolytic ubiquitin pathway with a parallel increase in free ubiquitin and ubiquitinated proteins in skeletal muscle of septic but not of control patients. In addition, those patients who would die from septic shock expressed more COX-2 and HO-1 proteins in muscle biopsies than did those patients who would survive. CONCLUSIONS: This study showed a marked involvement of local proinflammatory and antiinflammatory pathways and, more importantly, demonstrated the existence of an active ubiquitin proteolytic pathway in skeletal muscle of septic patients. Activation of ubiquitin pathway could be involved in sepsis-related muscle catabolism and wasting.

Adult↗
PubMed2003

Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure.

Although sepsis is the major cause of mortality and morbidity in the critically ill, precise mechanism(s) causing multiorgan dysfunction remain unclear. Findings of impaired oxygen utilization in septic patients and animals implicate nitric oxide-mediated inhibition of the mitochondrial respiratory chain. We recently reported a relationship between skeletal muscle mitochondrial dysfunction, clinical severity, and poor outcome in patients with septic shock. We thus developed a long-term, fluid-resuscitated, fecal peritonitis model utilizing male Wistar rats that closely replicates human physiological, biochemical, and histological findings with a 40% mortality. As with humans, the severity of organ dysfunction and eventual poor outcome were associated with nitric oxide overproduction and increasing mitochondrial dysfunction (complex I inhibition and ATP depletion). This was seen in both vital (liver) and nonvital (skeletal muscle) organs. Likewise, histological evidence of cell death was lacking, suggesting the possibility of an adaptive programmed shutdown of cellular function. This study thus supports the hypothesis that multiorgan dysfunction induced by severe sepsis has a bioenergetic etiology. Despite the well-recognized limitations of laboratory models, we found clear parallels between this long-term model and human disease characteristics that will facilitate future translational research.

Adenosine Monophosphate↗
PubMed2003

Variability of treatment duration for bacteraemia in the critically ill: a multinational survey.

OBJECTIVES: No definitive evidence is available to inform 'best' antibiotic practice for treating bacteraemia in the critically ill patient, either in terms of duration of therapy, or the use of mono- versus combination therapy. We therefore undertook a large-scale international survey to assess the variability of current practice. METHODS: A questionnaire was sent to membership lists of national and international intensive care societies. RESULTS: Responses from 254 intensive care units in 34 countries revealed a wide variation in antibiotic strategy for all types of bacteraemia, ranging from short course ( or=10 days) use of broad-spectrum combinations. Two factors were significantly associated with antibiotic prescribing practice, namely the country of origin (in those with >or=10 responders) and the level of microbiologist and/or infectious diseases specialist input. The greater the specialist input, the shorter the duration of therapy (P < 0.0001). CONCLUSIONS: The wide variability in antibiotic prescribing patterns suggests an urgent need to produce high-quality evidence to identify optimal antibiotic prescribing policies for bacteraemia in the critically ill patient.

Anti-Bacterial Agents↗