Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Meropenem in Neurocritical Care Patients: a Prospective Two-Center Study.

Morbidity and mortality related to ventriculitis in neurocritical care patients remain high. Antibiotic dose optimization may improve therapeutic outcomes. In this study, a population pharmacokinetic model of meropenem in infected critically ill patients was developed. We applied the final model to determine optimal meropenem dosing regimens required to achieve targeted cerebrospinal fluid exposures. Neurocritical care patients receiving meropenem and with a diagnosis of ventriculitis or extracranial infection were recruited from two centers to this study. Serial plasma and cerebrospinal fluid samples were collected and assayed. Population pharmacokinetic modeling and Monte Carlo dosing simulations were performed using Pmetrics. We sought to determine optimized dosing regimens that achieved meropenem cerebrospinal fluid concentrations above pathogen MICs for 40% of the dosing interval, or a higher target ratio of meropenem cerebrospinal fluid trough concentrations to pathogen MIC of ≥1. In total, 53 plasma and 34 cerebrospinal fluid samples were obtained from eight patients. Meropenem pharmacokinetics were appropriately described using a three-compartment model with linear plasma clearance scaled for creatinine clearance and cerebrospinal fluid penetration scaled for patient age. Considerable interindividual pharmacokinetic variability was apparent, particularly in the cerebrospinal fluid. Percent coefficients of variation for meropenem clearance from plasma and cerebrospinal fluid were 41.7% and 89.6%, respectively; for meropenem, the volume of distribution in plasma and cerebrospinal fluid values were 63.4% and 58.3%, respectively. High doses (up to 8 to 10 g/day) improved attainment of meropenem cerebrospinal fluid target exposures, particularly for less susceptible organisms (MICs, ≥0.25 mg/L). Standard meropenem doses of 2 g every 8 h may not achieve effective concentrations in cerebrospinal fluid in all critically ill patients. Higher doses, or alternative dosing methods (e.g., loading dose followed by continuous infusion) may be required to optimize cerebrospinal fluid exposures. Doses of up to 8 to 10 g/day either as intermittent boluses or continuous infusion would be suitable for patients with augmented renal clearance; lower doses may be considered for patients with impaired renal function as empirical suggestions. Ongoing dosing should be tailored to the individual patient circumstances. Notably, the study population was small and dosing recommendations may not be generalizable to all critically ill patients.

Pharmacokinetics of fluconazole and ganciclovir as combination antimicrobial chemotherapy on ECMO: a case report.

Extracorporeal membrane oxygenation (ECMO) can affect antimicrobial pharmacokinetics. This case report describes a 33-year-old male with newly diagnosed acquired immunodeficiency syndrome presenting in acute severe type 1 respiratory failure. On investigation, the patient had positive cultures for Candida albicans from respiratory specimens and high blood cytomegalovirus titres, and required venovenous ECMO therapy for refractory respiratory failure. Intravenous fluconazole (6 mg/kg, 24-h) and ganciclovir (5 mg/kg, 12-h) was commenced. Pre-oxygenator, post-oxygenator and arterial blood samples were collected after antibiotic administration, and were analysed for total fluconazole and ganciclovir concentrations. Although there was a 40% increase in the volume of distribution for fluconazole relative to healthy volunteers, the pharmacodynamic targets for prophylaxis were still met. The area under the curve exposure of ganciclovir (50.78 mg•h/L) achieved target thresholds. The ECMO circuit had no appreciable effect on achievement of therapeutic exposures of fluconazole and ganciclovir.

Population Pharmacokinetics of Levetiracetam in Patients with Traumatic Brain Injury and Subarachnoid Hemorrhage Exhibiting Augmented Renal Clearance.

BACKGROUND AND OBJECTIVE: Patients with severe trauma exhibit augmented renal clearance, which can alter the dosing requirement of renally eliminated drugs. This study aimed to develop a population pharmacokinetic model for levetiracetam in patients with severe traumatic brain injury and aneurysmal subarachnoid hemorrhage, and use it to describe optimal dosing regimens. METHODS: This was a prospective open-label observational study. Critically ill adult patients with severe traumatic brain injury or aneurysmal subarachnoid hemorrhage without renal dysfunction and receiving levetiracetam were eligible. Serial levetiracetam plasma concentrations were analyzed to develop a population pharmacokinetic model and perform dosing simulations. RESULTS: A two-compartment model best described the concentration-time data from 30 patients. The mean ± standard deviation parameter estimates were bioavailability (F) of 0.8 ± 0.2, absorption rate constant of 2.4 ± 2 h-1, clearance 2.5 ± 1.1 L/h, central volume of distribution 8.9 ± 3.0 L/h, and transfer rate constraints of 1.8 ± 1.1 h-1 from central to peripheral compartments and 0.7 ± 0.3 h-1 from peripheral to central compartments. For the simulated intermittent dosing regimens, on average, the median trough concentration reduced by 50% for every 40-mL/min/1.73 m2 increase in urinary creatinine clearance. Simulated doses of at least 6 g/day were required for some levels of augmented renal clearance. CONCLUSIONS: Patients with severe traumatic brain injury and aneurysmal subarachnoid hemorrhage with augmented renal clearance are at risk of not achieving target levetiracetam plasma concentrations. We suggest dose titration guided by measured creatinine clearance, and/or, therapeutic drug monitoring if available, to minimize the risk of seizures.

What the forks? A longitudinal quality improvement study tracking cutlery numbers in a public teaching and research hospital staff tearoom.

OBJECTIVES: To evaluate the circulation lifespan of forks and teaspoons in an institutional tearoom. DESIGN: Longitudinal quality improvement study, based on prospective tracking of marked teaspoons and forks. SETTING: Staff tearoom in a public teaching and research hospital, Brisbane. PARTICIPANTS: Tearoom patrons blinded to the purposes of the study. INTERVENTION: Stainless steel forks and teaspoons (18 each) were marked with red spots and introduced alongside existing cutlery (81 items) in the tearoom. MAIN OUTCOME MEASURES: Twice weekly count of marked forks and teaspoons for seven weeks; baseline and end of study count of all utensils on day 45. RESULTS: The loss of marked teaspoons (six of 18) was greater than that of forks (one of 18) by the conclusion of the study period (P = 0.038). The overall rate of utensil loss was 2.2 per 100 days for teaspoons and spoons, and -2.2 per 100 days for forks and knives. CONCLUSIONS: Teaspoon disappearance is a more substantial problem than fork migration in a multidisciplinary staff tearoom, and may reflect different kleptomaniacal or individual appropriation tendencies. If giving cutlery this Christmas, give teaspoons, not forks. The symbolism of fork rebirth or resurrection is appropriate for both Christmas and Easter, and forks are also mighty useful implements for eating cake!

Pharmacokinetics of Sulfamethoxazole and Trimethoprim During Venovenous Extracorporeal Membrane Oxygenation: A Case Report.

Extracorporeal membrane oxygenation (ECMO) therapy could affect drug concentrations via adsorption onto the oxygenator and/or associated circuit. We describe a case of a 33-year-old man with severe respiratory failure due to Pneumocystis jirovecii infection on a background of recently diagnosed human immunodeficiency virus infection. He required venovenous ECMO therapy for refractory respiratory failure. Intravenous sulfamethoxazole-trimethoprim (100 and 20 mg/kg/day) was administered in a dosing regimen every 6 hours. Pre-oxygenator, post-oxygenator, and arterial blood samples were collected after antibiotic administration and were analyzed for total sulfamethoxazole and trimethoprim concentrations. The peak sulfamethoxazole and trimethoprim concentrations were 122 mg/L and 5.3 mg/L, respectively. The volume of distribution for sulfamethoxazole was 0.37 and 2.30 L/kg for trimethoprim. The clearance for sulfamethoxazole was 0.35 ml/minute/kg and for trimethoprim was 1.64 ml/minute/kg. The pharmacokinetics of sulfamethoxazole and trimethoprim appear not to be affected by ECMO therapy, and dosing adjustment may not be required.

Pharmacokinetics of Total and Unbound Cefazolin during Veno-Arterial Extracorporeal Membrane Oxygenation: A Case Report.

Extra-corporeal membrane oxygenation (ECMO) therapy could affect effective drug concentrations via adsorption onto the oxygenator or associated circuit. We describe a case of a 25-year-old female who required a veno-arterial ECMO therapy for refractory cardiac arrest due to massive pulmonary embolism. She had mild renal dysfunction as a result of the cardiac arrest. A total of 2 g of intravenous cefazolin 8-hourly was administered. Pre- and post-oxygenator blood samples were collected at 0, 1, 4, and 8 h post antibiotic administration. Samples were analyzed for total and unbound cefazolin concentrations. Protein binding was ∼60%. Clearance was reduced due to impaired renal function. The pharmacokinetics of cefazolin appear to not be affected by ECMO therapy and dosing adjustment may not be required.

Amoxicillin-Clavulanate Dosing in the Intensive Care Unit: The Additive Effect of Renal Replacement Therapy in a Patient with Normal Kidney Function.

Dosing of amoxicillin-clavulanic acid in critical illness is difficult as ß-lactam pharmacokinetics are altered by physiological changes and therapies initiated in the intensive care unit such as renal replacement therapy (RRT). Successful treatment relies on sustaining a free antibiotic concentration above the minimum inhibitory concentration of the target pathogen (fT>MIC). We present a case of a patient treated with amoxicillin-clavulanic acid (1.2 g for 8 h) for an aspiration pneumonia. Dosing in this case was complicated by the necessity for RRT to treat a drug overdose with carbamazepine, despite normal native renal function. Antibiotic concentrations taken at steady state revealed a clearance of 14.6 L/h and a low fT>MIC (<40%). Analysis of the urine drug concentration suggested that 48% of clearance was via the native kidneys. This case illustrates that careful consideration of antibiotic dose and frequency is required in critically ill patients receiving RRT and highlights the need for further research in this patient group. In future similar cases, we would consider a dose of 2.2 g 6- or 8-hourly with early therapeutic drug monitoring.