Rachel F. Eyler

Antibiotic dosing in critically ill patients with acute kidney injury.

A common cause of acute kidney injury (AKI) is sepsis, which makes appropriate dosing of antibiotics in these patients essential. Drug dosing in critically ill patients with AKI, however, can be complicated. Critical illness and AKI can both substantially alter pharmacokinetic parameters as compared with healthy individuals or patients with end-stage renal disease. Furthermore, drug pharmacokinetic parameters are highly variable within the critically ill population. The volume of distribution of hydrophilic agents can increase as a result of fluid overload and decreased binding of the drug to serum proteins, and antibiotic loading doses must be adjusted upwards to account for these changes. Although renal elimination of drugs is decreased in patients with AKI, residual renal function in conjunction with renal replacement therapies (RRTs) result in enhanced drug clearance, and maintenance doses must reflect this situation. Antibiotic dosing decisions should be individualized to take into account patient-related, RRT-related, and drug-related factors. Efforts must also be made to optimize the attainment of antibiotic pharmacodynamic goals in this population.

Antibiotic Pharmacokinetic and Pharmacodynamic Considerations in Patients With Kidney Disease

Although pharmacokinetic changes occurring in kidney disease are well described, pharmacodynamics in kidney disease is rarely considered. Knowledge of pharmacodynamic principles can allow a clinician to maximize an antibiotics effectiveness while minimizing adverse effects and antibacterial resistance. An antibiotics pharmacokinetic and pharmacodynamic profiles should drive dose adjustment decisions in patients with kidney disease. For example, although the half-lives of beta-lactams and aminoglycosides are both prolonged in these patients, beta-lactams exhibit time-dependent antibacterial activity; consequently, maintenance doses should be smaller but given at the same interval. In contrast, aminoglycosides are concentration-dependent antibiotics; hence prolongation of the dosing interval while using larger doses may be advantageous. The timing of drug administration in relation to hemodialysis may be used to achieve specific pharmacodynamic goals. Aminoglycosides given before hemodialysis generate high peaks, whereas subsequent dialytic drug removal minimizes the area under the serum concentration-time curve, potentially decreasing the risk of developing toxicity. Furthermore, new dialysis prescribing patterns (eg, automated peritoneal dialysis, nocturnal dialysis) affect pharmacokinetic and pharmacodynamic parameters in ways not appreciated by clinicians. Studies quantifying the often considerable drug removal with these therapies, as well as efforts to identify pharmacodynamic targets in patients with kidney disease are essential. This paper reviews pharmacodynamic as well as pharmacokinetic issues that should be considered when prescribing antibiotics to treat infections in this population.

Pharmacokinetics of Ertapenem in Critically Ill Patients Receiving Continuous Venovenous Hemodialysis or Hemodiafiltration

ABSTRACT This study characterizes the pharmacokinetics of ertapenem, a carbapenem antibiotic, in critically ill adult subjects receiving continuous renal replacement therapy (CRRT). Eight critically ill patients with suspected/known Gram-negative infections receiving continuous venovenous hemodialysis (CVVHD) or continuous venovenous hemodiafiltration (CVVHDF) and ertapenem were enrolled. One gram of ertapenem was infused over 30 min. Predialyzer blood samples were drawn with the first dose of ertapenem from the hemodialysis tubing at time zero, 30 min, and 1, 2, 4, 8, 12, 18, and 24 h after the start of the ertapenem infusion. Effluent was collected at the same time points. Ertapenem total serum, unbound serum, and effluent concentrations from all eight subjects were used simultaneously to perform a population compartmental pharmacokinetic modeling procedure using NONMEM. Monte Carlo simulations were performed to evaluate the ability of several ertapenem dosing regimens (500 mg once daily, 750 mg once daily, 500 mg twice daily, and 1,000 mg once daily) to obtain effective unbound serum concentrations above 0.5, 1, and 2 μg/ml. For our simulated patients, all regimens produced unbound ertapenem concentrations above 2 μg/ml for 40% of the dosing interval for at least 96% of simulated patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00877370.)

Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in Critically Ill Patients Receiving Continuous Venovenous Hemodialysis and/or Extracorporeal Membrane Oxygenation

To investigate oseltamivir and oseltamivir carboxylate pharmacokinetics in critically ill patients who were receiving continuous venovenous hemodialysis (CVVHD) and/or extracorporeal membrane oxygenation (ECMO).

Risk Factors for Systemic Vancomycin Exposure Following Administration of Oral Vancomycin for the Treatment of Clostridium difficile Infection

To identify risk factors for systemic exposure to vancomycin (VAN) following administration of oral vancomycin (POV) for the treatment of Clostridium difficile infection (CDI).

Association of Oseltamivir Activation with Gender and Carboxylesterase 1 Genetic Polymorphisms.

Oseltamivir, an inactive anti‐influenza virus prodrug, is activated (hydrolysed) in vivo by carboxylesterase 1 (CES1) to its active metabolite oseltamivir carboxylate. CES1 functions are significantly associated with certain CES1 genetic variants and some non‐genetic factors. The purpose of this study was to investigate the effect of gender and several CES1 genetic polymorphisms on oseltamivir activation using a large set of individual human liver samples. CES1‐mediated oseltamivir hydrolysis and CES1 genotypes, including the G143E (rs71647871), rs2244613, rs8192935, the ‐816A>C (rs3785161) and the CES1P1/CES1P1VAR, were determined in 104 individual human livers. The results showed that hepatic CES1 protein expression in females was 17.3% higher than that in males (p = 0.039), while oseltamivir activation rate in the livers from female donors was 27.8% higher than that from males (p = 0.076). As for CES1 genetic polymorphisms, neither CES1 protein expression nor CES1 activity on oseltamivir activation was significantly associated with the rs2244613, rs8192935, ‐816A>C or CES1P1/CES1P1VAR genotypes. However, oseltamivir hydrolysis in the livers with the genotype 143G/E was approximately 40% of that with the 143G/G genotype (0.7 ± 0.2 versus 1.8 ± 1.1 nmole/mg protein/min, p = 0.005). In summary, the results suggest that hepatic oseltamivir activation appears to be more efficient in females than that in males, and the activation can be impaired by functional CES1 variants, such as the G143E. However, clinical implication of CES1 gender differences and pharmacogenetics in oseltamivir pharmacotherapy warrants further investigations.

In vitro glucose kinetics during continuous renal replacement therapy: implications for caloric balance in critically ill patients

Purpose To examine the impact of continuous renal replacement therapy (CRRT) on glucose kinetics and therefore caloric balance. Methods In vitro experiments were conducted to characterize glucose kinetics in a variety of CRRT modalities and prescriptions. Additional experiments evaluated the impact of citrate anticoagulation using anti-coagulant dextrose solution A (ACD-A) on CRRT glucose movement. A formula was developed to predict the glucose delivery to/from the patient per day of CRRT, and this data was extrapolated to determine the net caloric impact of CRRT. Results A total of 104 experiments were conducted with an overall glucose extraction coefficient of 1.04 (95% CI 1.03-1.05). CRRT-related glucose removal was directly related to effluent (dialysate and/or hemofiltration) rate and pre-filter blood glucose concentration, and inversely related to dialysis solution glucose concentration. In all modalities tested, CRRT resulted in a net negative glucose balance, with estimated caloric losses ranging between 20 kcal and 550 kcal depending on the conditions tested. The addition of ACD-A resulted in net glucose delivery in some conditions and a positive caloric balance of up to 470 kcal per day. Conclusions CRRT can have a significant effect on glucose balance and result in either significant daily caloric gains or losses, and this effect can be predicted based on CRRT prescription and patient characteristics. Clinicians should be aware of this potential impact when prescribing nutritional therapy to patients undergoing CRRT, as an imbalance in caloric feeding can adversely affect outcomes in critically ill patients.

The Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in a Critically Ill Pediatric Patient Receiving Extracorporeal Membrane Oxygenation and Continuous Venovenous Hemodialysis

This report details the pharmacokinetics of oseltamivir and oseltamivir carboxylate following administration of high-dose oseltamivir in a critically ill child receiving extracorporeal membrane oxygenation (ECMO) and continuous venovenous hemodialysis (CVVHD). A 6-year-old critically ill male patient suffering from a presumed viral illness was transferred to our institutions pediatric intensive care unit from an outside hospital after developing respiratory failure and cardiomegaly. ECMO and oseltamivir therapy were initiated upon admission, and CVVHD was started on hospital day 3. Pharmacokinetic sampling occurred at an oseltamivir dose of approximately 4 mg/kg on hospital day 6. The patients oseltamivir and oseltamivir carboxylate area under the plasma concentration time curves for the 12-hour dosing interval (AUC(0-12)) were 30.5 and 905 ng/mLhr, respectively. Drug clearance by CVVHD was 31.6 mL/min for oseltamivir and 26.9 mL/min for oseltamivir carboxylate. Pre- and postoxygenator oseltamivir and oseltamivir carboxylate plasma concentrations did not differ substantially. The patients oseltamivir carboxylate plasma concentrations remained well above the reported mean 50% inhibitory concentration for 2009 pandemic H1N1 virus. However, despite receiving twice the standard dose of oseltamivir, the oseltamivir carboxylate AUC(0-12) in our patient was less than that reported in noncritically ill pediatric subjects. The reduced oseltamivir carboxylate AUC(0-12) found in our patient was most likely due to decreased drug absorption.

Vancomycin use during left ventricular assist device support.

We reviewed the frequency and duration of vancomycin use during 93 left ventricular assist device placements. Vancomycin prophylaxis was administered for a mean duration (+/- standard deviation) of 10.5 +/- 11 days. Empirical vancomycin use was frequent, with a mean duration (+/- standard deviation) of therapy of 9.8 +/- 9 days (median, 8 days) given during 81 (87%) of the implantations. The most common indications for empirical vancomycin treatment were isolated leukocytosis or driveline drainage. Strategies to improve vancomycin use during left ventricular assist device support should be considered.

Thrombolysis for Massive Pulmonary Embolism in Pregnancy

Pregnant women are at high risk for venous thromboembolism, including pulmonary embolism (PE), given expected changes in coagulation, fibrinolysis, and venous blood flow. In fact, PE is the leading cause of maternal death in the United States. Nonpregnant patients who develop PE with hypotension or show signs of deterioration after anticoagulation receive thrombolytics as a standard of care. Pregnant women, however, have been excluded from clinical trials with thrombolytics, and all data available in this population are published as case reports or case series. We reviewed all reports of thrombolytics, systemic or catheter directed, used in pregnant patients with massive PE. This article summarizes the risks for thromboembolism in pregnancy, compares and contrasts thrombolytic agents in this setting, and provides a recommendation for management of massive PE in this special population. Overall, reports suggest that the use of these agents is associated with beneficial outcomes and a relatively low risk of complications. The quality of this evidence is low, and clinical judgment is required to assess individual patients for risks versus benefits of thrombolysis.