Oxazolidinones are a class of synthetic antimicrobial agents with potent activity against a wide range of multidrug-resistant Gram-positive pathogens including methicillin-resistant Staphylococcus ...aureus and vancomycin-resistant enterococci. Oxazolidinones exhibit their antibacterial effects by inhibiting protein synthesis acting on the ribosomal 50S subunit of the bacteria and thus preventing formation of a functional 70S initiation complex. Currently, two oxazolidinones have been approved by the US Food and Drug Administration: linezolid and more recently tedizolid. Other oxazolidinones are currently under investigation in clinical trials. These antimicrobial agents exhibit a favourable pharmacokinetic profile with an excellent bioavailability and a good tissue and organ penetration. In-vitro susceptibility studies have shown that oxazolidinones are bacteriostatic against enterococci and staphylococci, and bactericidal for the majority of strains of streptococci. In the context of emergence of resistance to glycopeptides, oxazolidinones have become an effective alternative to vancomycin treatment frequently associated with nephrotoxicity. However, oxazolidinones, and linezolid in particular, are associated with significant adverse events, myelosuppression representing the main unfavourable side effect. More recently, tedizolid has been shown to effectively treat acute bacterial skin and skin structure infections. This newer oxazolidinone offers the advantages of once-daily dosing and a better safety profile in healthy volunteer studies (fewer gastrointestinal and haematological side effects). The potential use of tedizolid for other infections that could require longer therapy warrants further studies for positioning this new oxazolidinone in the available antimicrobial armamentarium. Moreover, other oxazolidinones are currently under active investigation.
To discuss the altered pharmacokinetic properties of selected antibiotics in critically ill patients and to develop basic dose adjustment principles for this patient population.
PubMed, EMBASE, and ...the Cochrane-Controlled Trial Register.
Relevant papers that reported pharmacokinetics of selected antibiotic classes in critically ill patients and antibiotic pharmacodynamic properties were reviewed. Antibiotics and/or antibiotic classes reviewed included aminoglycosides, beta-lactams (including carbapenems), glycopeptides, fluoroquinolones, tigecycline, linezolid, lincosamides, and colistin.
Antibiotics can be broadly categorized according to their solubility characteristics which can, in turn, help describe possible altered pharmacokinetics that can be caused by the pathophysiological changes common to critical illness. Hydrophilic antibiotics (e.g., aminoglycosides, beta-lactams, glycopeptides, and colistin) are mostly affected with the pathphysiological changes observed in critically ill patients with increased volumes of distribution and altered drug clearance (related to changes in creatinine clearance). Lipophilic antibiotics (e.g., fluoroquinolones, macrolides, tigecycline, and lincosamides) have lesser volume of distribution alterations, but may develop altered drug clearances. Using antibiotic pharmacodynamic bacterial kill characteristics, altered dosing regimens can be devised that also account for such pharmacokinetic changes.
Knowledge of antibiotic pharmacodynamic properties and the potential altered antibiotic pharmacokinetics in critically ill patients can allow the intensivist to develop individualized dosing regimens. Specifically, for renally cleared drugs, measured creatinine clearance can be used to drive many dose adjustments. Maximizing clinical outcomes and minimizing antibiotic resistance using individualized doses may be best achieved with therapeutic drug monitoring.
Controversy reigns as to how protein binding changes alter the time course of unbound drug concentrations in patients. Given that the unbound concentration is responsible for drug efficacy and ...potential drug toxicity, this area is of significant interest to clinicians and academics worldwide. The present uncertainty means that many questions relating to this area exist, including "How important is protein binding?", "Is protein binding always constant?", "Do pH and temperature changes alter binding?" and "How do protein binding changes affect dosing requirements?". In this paper, we seek to address these questions and consider the data associated with altered pharmacokinetics in the presence of changes in protein binding and the clinical consequences that these may have on therapy, using examples from the critical care area. The published literature consistently indicates that a change in the protein binding and unbound concentrations of some drugs are common in certain specific patient groups such as the critically ill. Changes in pharmacokinetic parameters, including clearance and apparent volume of distribution (V(d)), may be dramatic. Drugs with high protein binding, high intrinsic clearance (e.g. clearance by glomerular filtration) and where dosing is not titrated to effect are most likely to be affected in a clinical context. Drugs such as highly protein bound antibacterials with multiple half-lives within a dosing interval and that have some level of renal clearance, such as ertapenem, teicoplanin, ceftriaxone and flucloxacillin, are commonly affected. In response to these challenges, clinicians need to adapt dosing regimens rationally based on the pharmacokinetic/pharmacodynamic characteristics of the drug. We propose that further pharmacokinetic modelling-based research is required to enable the design of robust dosing regimens for drugs affected by altered protein binding.
The ability to visualize endogenous proteins in living neurons provides a powerful means to interrogate neuronal structure and function. Here we generate recombinant antibody-like proteins, termed ...Fibronectin intrabodies generated with mRNA display (FingRs), that bind endogenous neuronal proteins PSD-95 and Gephyrin with high affinity and that, when fused to GFP, allow excitatory and inhibitory synapses to be visualized in living neurons. Design of the FingR incorporates a transcriptional regulation system that ties FingR expression to the level of the target and reduces background fluorescence. In dissociated neurons and brain slices, FingRs generated against PSD-95 and Gephyrin did not affect the expression patterns of their endogenous target proteins or the number or strength of synapses. Together, our data indicate that PSD-95 and Gephyrin FingRs can report the localization and amount of endogenous synaptic proteins in living neurons and thus may be used to study changes in synaptic strength in vivo.
•Recombinant intrabodies (FingRs) generated with mRNA display bind PSD-95 or Gephyrin•PSD-95 and Gephyrin FingRs accurately label endogenous targets in living neurons•Transcriptional control matches expression of FingRs to targets, reducing background•PSD-95 and Gephyrin FingRs do not affect neuronal morphology or function
New methods are needed to monitor synaptic structure in vivo in real time. Gross et al. report the generation of genetically encoded intrabodies (FingRs) that bind Gephryn and PSD-95 and can be used to fluorescently label inhibitory and excitatory synapses.
Purpose
This Position Paper aims to review and discuss the available data on therapeutic drug monitoring (TDM) of antibacterials, antifungals and antivirals in critically ill adult patients in the ...intensive care unit (ICU). This Position Paper also provides a practical guide on how TDM can be applied in routine clinical practice to improve therapeutic outcomes in critically ill adult patients.
Methods
Literature review and analysis were performed by Panel Members nominated by the endorsing organisations, European Society of Intensive Care Medicine (ESICM), Pharmacokinetic/Pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID), International Association for Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) and International Society of Antimicrobial Chemotherapy (ISAC). Panel members made recommendations for whether TDM should be applied clinically for different antimicrobials/classes.
Results
TDM-guided dosing has been shown to be clinically beneficial for aminoglycosides, voriconazole and ribavirin. For most common antibiotics and antifungals in the ICU, a clear therapeutic range has been established, and for these agents, routine TDM in critically ill patients appears meritorious. For the antivirals, research is needed to identify therapeutic targets and determine whether antiviral TDM is indeed meritorious in this patient population. The Panel Members recommend routine TDM to be performed for aminoglycosides, beta-lactam antibiotics, linezolid, teicoplanin, vancomycin and voriconazole in critically ill patients.
Conclusion
Although TDM should be the standard of care for most antimicrobials in every ICU, important barriers need to be addressed before routine TDM can be widely employed worldwide.
Continuous renal replacement therapy (CRRT) may alter antibiotic pharmacokinetics and increase the risk of incorrect dosing. In a nested cohort within a large randomized controlled trial, we assessed ...the effect of higher (40 mL/kg per hour) and lower (25 mL/kg per hour) intensity CRRT on antibiotic pharmacokinetics.
We collected serial blood samples to measure ciprofloxacin, meropenem, piperacillin-tazobactam, and vancomycin levels. We calculated extracorporeal clearance (CL), systemic CL, and volume of distribution (Vd) by non-linear mixed-effects modelling. We assessed the influence of CRRT intensity and other patient factors on antibiotic pharmacokinetics.
We studied 24 patients who provided 179 pairs of samples. Extracorporeal CL increased with higher-intensity CRRT but the increase was significant for vancomycin only (mean 28 versus 22 mL/minute; P = 0.0003). At any given prescribed CRRT effluent rate, extracorporeal CL of individual antibiotics varied widely, and the effluent-to-plasma concentration ratio decreased with increasing effluent flow. Overall, systemic CL varied to a greater extent than Vd, particularly for meropenem, piperacillin, and tazobactam, and large intra-individual differences were also observed. CRRT dose did not influence overall (systemic) CL, Vd, or half-life. The proportion of systemic CL due to CRRT varied widely and was high in some cases.
In patients receiving CRRT, there is great variability in antibiotic pharmacokinetics, which complicates an empiric approach to dosing and suggests the need for therapeutic drug monitoring. More research is required to investigate the apparent relative decrease in clearance at higher CRRT effluent rates.
ClinicalTrials.gov NCT00221013. Registered 14 September 2005.
Drugs are key weapons that clinicians have to battle against the profound pathologies encountered in critically ill patients. Antibiotics in particular are commonly used and can improve patient ...outcomes dramatically. Despite this, there are strong opportunities for further reducing the persisting poor outcomes for infected critically ill patients. However, taking these next steps for improving patient care requires a new approach to antibiotic therapy. Giving the right dose is highly likely to increase the probability of clinical cure from infection and suppress the emergence of resistant pathogens. Furthermore, in some patients with higher levels of sickness severity, reduced mortality from an optimized approach to antibiotic use could also occur. To enable optimized dosing, the use of customized dosing regimens through either evidence-based dosing nomograms or preferably through the use of dosing software supplemented by therapeutic drug monitoring data should be embedded into daily practice. These customized dosing regimens should also be given as soon as practicable as reduced time to initiation of therapy has been shown to improve patient survival, particularly in the presence of septic shock. However, robust data supporting these logical approaches to therapy, which may deliver the next step change improvement for treatment of infections in critically ill patients, are lacking. Large prospective studies of patient survival and health system costs are now required to determine the value of customized antibiotic dosing, that is, giving the right dose at the right time.
To describe the achievement of unbound β-lactam antibiotic concentration targets in a therapeutic drug monitoring (TDM) programme in critically ill patients, and the factors associated with failure ...to achieve a target concentration.
Plasma samples and clinical data were obtained for analysis from a single centre prospectively. Unbound concentrations of ceftriaxone, cefazolin, meropenem, ampicillin, benzylpenicillin, flucloxacillin and piperacillin were directly measured using ultracentrifugation. Factors associated with the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets or negative clinical outcomes were evaluated with binomial logistic regression.
TDM data from 330 patients, and 369 infection episodes, were included. The range of doses administered was 99.4% ± 45.1% relative to a standard daily dose. Dose increases were indicated in 33.1% and 63.4% of cases to achieve PK/PD targets of 100% fT>MIC and 100% fT>4×MIC, respectively. Dose reduction was indicated in 17.3% of cases for an upper PK/PD threshold of 100% fT>10×MIC. Higher protein bound β-lactams (ceftriaxone and benzylpenicillin) had better therapeutic target attainment (P < 0.01), but were prone to excessive dosing. Augmented renal clearance (calculated CLCR >130 mL/min) increased the odds of failure to achieve 100% fT>MIC and 100% fT>4×MIC (OR 2.47 and 3.05, respectively; P < 0.01).
Measuring unbound concentrations of β-lactams as part of a routine TDM programme is feasible and demonstrates that a large number of critically ill patients do not achieve predefined PK/PD targets. The clinical significance of this finding is unknown due to the lack of correlation between PK/PD findings and clinical outcomes.
Successful antibiotic therapy in the critically ill requires sufficient drug concentrations at the site of infection that kill or suppress bacterial growth. The relationship between antibiotic ...exposure and achieving the above effects is referred to as pharmacokinetics/pharmacodynamics (PK/PD). The associated indices therefore provide logical targets for optimal antibiotic therapy. While dosing regimens to achieve such targets have largely been established from studies in animals and non-critically ill patients, they are often poorly validated in the ICU. Endothelial dysfunction, capillary leak, altered major organ blood flow, deranged plasma protein concentrations, extremes of body habitus, the application of extracorporeal support modalities, and a higher prevalence of intermediate susceptibility, independently, and in combination, significantly confound successful antibiotic treatment in this setting. As such, the prescription of standard doses are likely to result in sub-therapeutic concentrations, which in turn may promote treatment failure or the selection of resistant pathogens. This review article considers these issues in detail, summarizing the key changes in antibiotic PK/PD in the critically ill, and suggesting alternative dosing strategies that may improve antibiotic therapy in these challenging patients.
Highlights • Augmented renal clearance (ARC) is a prevalent condition in the critically ill. • ARC may result in sub-therapeutic exposure of renally eliminated antibiotics. • Beta-lactams are ...particularly affected due to their pharmacokinetic and pharmacodynamic characteristics. • Dose optimization is necessary to circumvent the influence of ARC. • Therapeutic drug monitoring may be necessary to guide dose optimization.
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