Protein binding of β-lactam antibiotics in critically Ill patients: can we successfully predict unbound concentrations?

The use of therapeutic drug monitoring (TDM) to optimize beta-lactam dosing in critically ill patients is growing in popularity, although there are limited data describing the potential impact of altered protein binding on achievement of target concentrations. The aim of this study was to compare the measured unbound concentration to the unbound concentration predicted from published protein binding values for seven beta-lactams using data from blood samples obtained from critically ill patients. From 161 eligible patients, we obtained 228 and 220 plasma samples at the midpoint of the dosing interval and trough, respectively, for ceftriaxone, cefazolin, meropenem, piperacillin, ampicillin, benzylpenicillin, and flucloxacillin. The total and unbound beta-lactam concentrations were measured using validated methods. Variabilities in both unbound and total concentrations were marked for all antibiotics, with significant differences being present between measured and predicted unbound concentrations for ceftriaxone and for flucloxacillin at the mid-dosing interval (

Ampicillin/sulbactam: Its potential use in treating infections in critically ill patients

The purpose of this paper was to review the potential utility of ampicillin/sulbactam (SAM) as a therapy for serious infections in critically ill patients. Data for this review were identified by searches of PubMed and of the reference lists of the included articles. We found that SAM appears to have a number of characteristics that support its use in the treatment of serious infections in critically ill patients. SAM demonstrates extensive penetration into many infection sites, supporting its use in a wide range of infection types. Microbiologically, sulbactam has strong intrinsic antibiotic activity against multidrug-resistant (MDR) bacteria, including Acinetobacter baumannii, which supports its use for the treatment of infections mediated by this pathogen. Of some concern, there have been reports showing a decline in susceptibility of some bacteria to SAM. As such, use of lower doses (4/2 g/day), particularly for MDR A. baumannii, has been linked with a 30% reduced success rate in critically ill patients. The therapeutic challenges for ensuring achievement of optimal dosing of SAM result partly from bacterial susceptibility but also from the pharmacokinetic (PK) alterations common to beta-lactam agents in critical illness. These PK changes are likely to reduce the ability of standard dosing to achieve the concentrations observed in non-critically ill patients. Optimisation of therapy may be more likely with the use of higher doses, administration by 4 h infusion or by combination therapy, particularly for the treatment of infections caused by MDR pathogens. (c) 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved

Pharmacokinetics of meropenem and piperacillin in critically ill patients with indwelling surgical drains

Meropenem and piperacillin are two commonly prescribed antibiotics in critically ill surgical patients. To date, the pharmacokinetics of these antibiotics in the presence of indwelling abdominal surgical drains is poorly defined. This was a prospective pharmacokinetic study of meropenem and piperacillin. Serial plasma, urine and surgical drain fluid samples were collected over one dosing interval of antibiotic treatment in ten patients (meropenem, n = 5; piperacillin n = 5). Drug concentrations were measured using a validated high-performance liquid chromatography assay. Median (interquartile range) pharmacokinetic parameter estimates for meropenem were as follows: area under concentration-time curve (AUC), 128.7 mg h/L (95.3-176.7 mg h/L); clearance (CL), 5.7 L/h (5.1-10.5 L/h); volume of distribution (Vd), 0.41 L/kg (0.35-0.56 L/kg); AUC ratio (drain: plasma), 0.2 (0.1-0.2); and calculated antibiotic clearance via surgical drain, 3.8% (2.8-5.4%). For piperacillin, unbound pharmacokinetic results were as follows; AUC, 344.3 mg h/L (341.1-348.4 mg h/L); CL, 13.1 L/h (12.9-13.2 L/h); Vd, 0.63 L/kg (0.38-1.28 L/kg); AUC ratio (drain: plasma), 0.2 (0.2-0.3); and calculated antibiotic clearance via surgical drain 8.2% (3.3-14.0%). A linear correlation was present between the percentage of antibiotic cleared through the drain and the volume of surgical drain fluid output for meropenem (r(2) = 0.89; P = 0.05) and piperacillin (r(2) = 0.63; P = 0.20). Meropenem and piperacillin have altered pharmacokinetics in critically ill patients with indwelling surgical drains. We propose that only when very high drain fluid output is present (>1000 mL/day) would an additional dose of antibiotic be necessary. (C) 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved

Antimicrobial de-escalation in the critically ill patient and assessment of clinical cure: the DIANA study

Purpose: The DIANA study aimed to evaluate how often antimicrobial de-escalation (ADE) of empirical treatment is performed in the intensive care unit (ICU) and to estimate the effect of ADE on clinical cure on day 7 following treatment initiation. Methods: Adult ICU patients receiving empirical antimicrobial therapy for bacterial infection were studied in a prospective observational study from October 2016 until May 2018. ADE was defined as (1) discontinuation of an antimicrobial in case of empirical combination therapy or (2) replacement of an antimicrobial with the intention to narrow the antimicrobial spectrum, within the first 3 days of therapy. Inverse probability (IP) weighting was used to account for time-varying confounding when estimating the effect of ADE on clinical cure. Results: Overall, 1495 patients from 152 ICUs in 28 countries were studied. Combination therapy was prescribed in 50%, and carbapenems were prescribed in 26% of patients. Empirical therapy underwent ADE, no change and change other than ADE within the first 3 days in 16%, 63% and 22%, respectively. Unadjusted mortality at day 28 was 15.8% in the ADE cohort and 19.4% in patients with no change [p = 0.27; RR 0.83 (95% CI 0.60-1.14)]. The IP-weighted relative risk estimate for clinical cure comparing ADE with no-ADE patients (no change or change other than ADE) was 1.37 (95% CI 1.14-1.64). Conclusion: ADE was infrequently applied in critically ill-infected patients. The observational effect estimate on clinical cure suggested no deleterious impact of ADE compared to no-ADE. However, residual confounding is likely