Variable Linezolid Exposure in Intensive Care Unit Patients-Possible Role of Drug-Drug Interactions.

BACKGROUND: Standard doses of linezolid may not be suitable for all patient groups. Intensive care unit (ICU) patients in particular may be at risk of inadequate concentrations. This study investigated variability of drug exposure and its potential sources in this population. METHODS: Plasma concentrations of linezolid were determined by high-performance liquid chromatography in a convenience sample of 20 ICU patients treated with intravenous linezolid 600 mg twice daily. Ultrafiltration applying physiological conditions (pH 7.4/37°C) was used to determine the unbound fraction. Individual pharmacokinetic (PK) parameters were estimated by population PK modeling. As measures of exposure to linezolid, area under the concentration-time curve (AUC) and trough concentrations (Cmin) were calculated and compared with published therapeutic ranges (AUC 200-400 mg*h/L, Cmin 2-10 mg/L). Coadministered inhibitors or inducers of cytochrome P450 and/or P-glycoprotein were noted. RESULTS: Data from 18 patients were included into the PK evaluation. Drug exposure was highly variable (median, range: AUC 185, 48-618 mg*h/L, calculated Cmin 2.92, 0.0062-18.9 mg/L), and only a minority of patients had values within the target ranges (6 and 7, respectively). AUC and Cmin were linearly correlated (R = 0.98), and classification of patients (underexposed/within therapeutic range/overexposed) according to AUC or Cmin was concordant in 15 cases. Coadministration of inhibitors was associated with a trend to higher drug exposure, whereas 3 patients treated with levothyroxine showed exceedingly low drug exposure (AUC ∼60 mg*h/L, Cmin <0.4 mg/L). The median unbound fraction in all 20 patients was 90.9%. CONCLUSIONS: Drug exposure after standard doses of linezolid is highly variable and difficult to predict in ICU patients, and therapeutic drug monitoring seems advisable. PK drug-drug interactions might partly be responsible and should be further investigated; protein binding appears to be stable and irrelevant.

Protein binding characteristics and pharmacokinetics of ceftriaxone in intensive care unit patients.

AIMS: The aim of the present study was to assess the pharmacokinetics of total and unbound ceftriaxone in intensive care unit (ICU) patients and its protein binding characteristics. METHODS: Twenty patients (m/f 15/5, age 25-86 years, body weight 60-121 kg, APACHE II 7-40, estimated glomerular filtration rate 19-157 ml min(-1) , albumin 11.7-30.1 g l(-1) , total bilirubin <0.1-36.1 mg dl(-1) ) treated with intravenous ceftriaxone were recruited from two ICUs. Timed plasma samples were obtained using an opportunistic study protocol. Ceftriaxone concentrations were determined by high-performance liquid chromatography; unbound concentrations were determined after ultrafiltration using a new method which maintains physiological pH and temperature. The pharmacokinetics was described by a one-compartment model, the protein-binding characteristics by Michaelis-Menten kinetics. RESULTS: For total drug, the volume of distribution was 20.2 l (median; interquartile range 15.6-24.5 l), the half-life 14.5 h (10.0-25.5 h) and the clearance 0.96 l h(-1) (0.55-1.28 l h(-1) ). The clearance of unbound drug was 1.91 l h(-1) (1.46-6.20 l h(-1) ) and linearly correlated with estimated glomerular filtration rate (slope 0.85, y-intercept 0.24 l h(-1) , r(2) = 0.70). The unbound fraction was higher in ICU patients (33.0%; 20.2-44.5%) than reported in healthy volunteers, particularly when renal impairment or severe hyperbilirubinaemia was present. In all patients, unbound concentrations during treatment with ceftriaxone 2 g once daily remained above the EUCAST susceptibility breakpoint (≤1 mg l(-1) ) throughout the whole dosing interval. CONCLUSIONS: Protein binding of ceftriaxone is reduced and variable in ICU patients due to hypoalbuminaemia, but also to altered binding characteristics. Despite these changes, the pharmacokinetics of unbound ceftriaxone is governed by renal function. For patients with normal or reduced renal function, standard doses are sufficient.

Spectrum adequacy of antibiotic regimens for secondary peritonitis: a retrospective analysis in intermediate and intensive care unit patients.

BACKGROUND: Secondary peritonitis requires surgical source control and adequate antimicrobial treatment. Antimicrobial regimens are usually selected according to local susceptibility data of individual pathogens against single agents, but this neglects both the polymicrobial nature of the infection and the use of combination therapy. We analysed the probability of common regimens to cover all relevant pathogens isolated in one patient ("spectrum adequacy rate", SAR) in a real-life data set. METHODS: Data from 242 patients with secondary peritonitis (88 community acquired, 154 postoperative cases) treated in our IMCU/ICU were obtained retrospectively. The relative frequency of pathogens, resistance rates and the SAR were analysed using the free software R. RESULTS: Enterococci were isolated in 47.1 % of all patients, followed by Escherichia coli (42.6 %), other enterobacteriaceae (33.1 %), anaerobes (29.8 %) and Candida spp. (28.9 %). Resistance patterns were consistent with general surveillance data from our hospital. The susceptibility rates and SAR were lower in postoperative than in community acquired cases. The following regimens yielded a SAR > 95 % when enterobacteriaceae only were considered: piperacillin/tazobactam + gentamicin, cefotaxim (only for community acquired cases), cefotaxim + gentamicin, meropenem, tigecycline + gentamicin or tigecycline + ciprofloxaxin. When enterococci were also considered, all betalactam based regimens required combination with vancomycin or linezolid for a SAR > 95 %, whereas TGC based regimens were not compromised. As for Candida spp., the SAR of fluconazole was 81.9-87.5 %. CONCLUSIONS: This study demonstrates a rational approach to assess the adequacy of antimicrobial regimens in secondary peritonitis, which may help to adjust local guidelines or to select candidate regimens for clinical studies.

Accidentally ingested toothpicks causing severe gastrointestinal injury: a practical guideline for diagnosis and therapy based on 136 case reports.

BACKGROUND: Ingested toothpicks are a relatively rare event, but may cause serious gut injuries with peritonitis, sepsis, or death. Numerous case reports describing the clinical course in this setting are available but there is no concise guideline. The aim of the present study was to develop practical guidelines to aid clinicians in the diagnosis and management of acute tooth pick ingestion. METHOD: Our Medline search identified 116 publications containing case reports of ingested toothpicks. We then performed a retrospective analysis of patients' characteristics, medical history, diagnostics, therapy, and clinical outcome. RESULTS: A total of 136 cases (74 % male, age 52 [5-92] years) have been reported in the literature. From the available information, more than 50 % (n = 48) of patients were not aware of having swallowed a toothpick. The most common presenting symptoms were abdominal pain (82 %), fever (39 %), and nausea (31 %). The toothpick caused gut perforation in 79 % of all patients. The locations of toothpicks prior removal were esophagus (2 %), stomach (20 %), duodenum (23 %), small intestine (18 %), and large intestine (37 %). The diagnostic procedures included endoscopy (63 %), computed tomography scan (63 %), and ultrasound (47 %); however, in 35 % of cases these investigations failed to detect the toothpick. Therapy was surgery in most cases (58 %). The overall mortality was 9.6 %. CONCLUSIONS: Toothpick ingestion is a medical emergency. Perforations of the intestine are common and the associated mortality is high. Adequate therapy depends on localization of the toothpick in the gastrointestinal tract. Ingested toothpicks should be kept in mind as an important differential diagnosis in patients with acute abdomen.

The Northern California Chronic Care Network for Dementia.

The Northern California Chronic Care Network for Dementia brings together Northern California's major providers of managed care, community-based care, consumer education, and advocacy in new partnerships to improve the care of persons with dementia enrolled in managed care plans and their family caregivers. These partnerships are part of a national initiative entitled the Chronic Care Network for Alzheimer's Disease (CCN/AD) sponsored by the National Chronic Care Consortium and the Alzheimer's Association. This initiative selected eight promising provider-consumer partnerships across the country to implement and evaluate a new model of coordinated care for people with dementia and their families. This paper describes the Northern California network's partnerships and its intervention and challenges. The intervention is grounded in the key components of the CCN/AD model: "identification of patients with possible dementia, diagnostic assessment, care management and family caregiver information and support." These components, in turn, are translated into protocols and pathways designed to create timely, comprehensive, appropriate, and effective systems of care services that address the unique needs of dementia patients and their caregivers over the course of the disease.