Marta Ulldemolins

Therapeutic drug monitoring of β-lactams in critically ill patients: proof of concept

The extreme pharmacokinetic behaviour of drugs sometimes observed in critically ill patients poses a significant threat to the achievement of optimal antibiotic treatment outcomes. Scant information on beta-lactam antibiotic therapeutic drug monitoring (TDM) is available. The objective of this prospective study was to evaluate the practicality and utility of a beta-lactam TDM programme in critically ill patients. TDM was performed twice weekly on all eligible patients at a 30-bed tertiary referral critical care unit. Blood concentrations were determined by fast-throughput high-performance liquid chromatography (HPLC) assays and were available within 12h of sampling. Dose adjustment was instituted if the trough or steady-state blood concentration was below 4-5x the minimum inhibitory concentration (MIC) or above 10x MIC. A total of 236 patients were subject to TDM over an 11-month period. The mean+/-standard deviation age was 53.5+/-18.3 years. Dose adjustment was required in 175 (74.2%) of the patients, with 119 of these patients (50.4%) requiring dose increases after the first TDM. For outcome of therapy, 206 (87.3%) courses resulted in a positive treatment outcome and there were 30 (12.7%) treatment failures observed including 14 deaths and 15 courses requiring escalation to broader-spectrum agents; 1 course was ceased due to an adverse drug reaction. Using binomial logistic regression, only an elevated Acute Physiology and Chronic Health Evaluation (APACHE) II score (P<0.01) and elevated plasma creatinine concentration (P=0.05) were found to be predictive of mortality. In conclusion, further research is required to determine definitively whether achievement of optimal beta-lactam pharmacodynamic targets improves clinical outcomes.

The Effects of Hypoalbuminaemia on Optimizing Antibacterial Dosing in Critically Ill Patients

Low serum albumin levels are very common in critically ill patients, with reported incidences as high as 40–50%. This condition appears to be associated with alterations in the degree of protein binding of many highly protein-bound antibacterials, which lead to altered pharmacokinetics and pharmacodynamics, although this topic is infrequently considered in daily clinical practice. The effects of hypoalbuminaemia on pharmacokinetics are driven by the decrease in the extent of antibacterial bound to albumin, which increases the unbound fraction of the drug. Unlike the fraction bound to plasma proteins, the unbound fraction is the only fraction available for distribution and clearance from the plasma (central compartment). Hence, hypoalbuminaemia is likely to increase the apparent total volume of distribution (Vd) and clearance (CL) of a drug, which would translate to lower antibacterial exposures that might compromise the attainment of pharmacodynamic targets, especially for time-dependent antibacterials. The effect of hypoalbuminaemia on unbound concentrations is also likely to have an important impact on pharmacodynamics, but there is very little information available on this area.The objectives of this review were to identify the original research papers that report variations in the highly protein-bound antibacterial pharmacokinetics (mainly Vd and CL) in critically ill patients with hypoalbuminaemia and without renal failure, and subsequently to interpret the consequences for antibacterial dosing. All relevant articles that described the pharmacokinetics and/or pharmacodynamics of highly protein-bound antibacterials in critically ill patients with hypoalbuminaemia and conserved renal function were reviewed.We found that decreases in the protein binding of antibacterials in the presence of hypoalbuminaemia are frequently observed in critically ill patients. For example, the Vd and CL of ceftriaxone (85–95% protein binding) in hypoalbuminaemic critically ill patients were increased 2-fold. A similar phenomenon was reported with ertapenem (85–95% protein binding), which led to failure to attain pharmacodynamic targets (40% time for which the concentration of unbound [free] antibacterial was maintained above the minimal inhibitory concentration [fT>MIC] of the bacteria throughout the dosing interval). The Vd and CL of other highly protein-bound antibacterials such as teicoplanin, aztreonam, fusidic acid or daptomycin among others were significantly increased in critically ill patients with hypoalbuminaemia compared with healthy subjects.Increased antibacterial Vd appeared to be the most significant pharmacokinetic effect of decreased albumin binding, together with increased CL. These pharmacokinetic changes may result in decreased achievement of pharmacodynamic targets especially for time-dependent antibacterials, resulting in sub-optimal treatment. The effects on concentration-dependent antibacterial pharmacodynamics are more controversial due to the lack of data on this topic. In conclusion, altered antibacterial-albumin binding in the presence of hypoalbuminaemia is likely to produce significant variations in the pharmacokinetics of many highly protein-bound antibacterials. Dose adjustments of these antibacterials in critically ill patients with hypoalbuminaemia should be regarded as another step for antibacterial dosing optimization. Moreover, some of the new antibacterials in development exhibit a high level of protein binding although hypoalbuminaemia is rarely considered in clinical trials in critically ill patients. Further research that defines dosing regimens that account for such altered pharmacokinetics is recommended.

Flucloxacillin dosing in critically ill patients with hypoalbuminaemia: special emphasis on unbound pharmacokinetics

OBJECTIVES To describe the total and unbound plasma concentration-time profiles for highly protein-bound flucloxacillin (95%-97% protein binding) in critically ill patients with hypoalbuminaemia and without severe renal dysfunction, and to use population pharmacokinetic modelling and Monte Carlo simulations to assess the probability of target attainment against an MIC distribution. PATIENTS AND METHODS Ten patients with hypoalbuminaemia and receiving flucloxacillin as part of therapy were enrolled. Sixty-seven total, 67 unbound plasma and 10 urine samples were collected and analysed. Population pharmacokinetic modelling of unbound plasma data and Monte Carlo simulations were then undertaken with NONMEM. Non-compartmental pharmacokinetic analysis was performed for total plasma concentrations. RESULTS Total flucloxacillin V was increased in critically ill patients with hypoalbuminaemia 2-fold compared with healthy volunteer data. Unbound flucloxacillin concentrations after 2 g bolus fell below 1 mg/L 4 h after the end of the infusion, providing evidence that standard dosing would be insufficient for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) (MIC = 2 mg/L). Monte Carlo simulations suggest that continuous infusion of 8 g/24 h flucloxacillin would enable 100% successful attainment of the pharmacodynamic target, 50% fT( > MIC). For more aggressive targets (4-5x MIC for 100% fT( > MIC)), continuous infusion of higher doses (i.e. 12 g/24 h) would be required. CONCLUSIONS Administration of standard doses by intermittent bolus is likely to result in underdosing, and continuous infusion of higher doses is more likely to achieve pharmacokinetic-pharmacodynamic targets for the treatment of infections caused by the most common wild type of MSSA. Our data emphasize the importance of using unbound concentrations for determining dosage regimens for highly bound antibiotics.

The relevance of drug volume of distribution in antibiotic dosing.

Despite the importance of early an appropriate therapy for the outcomes of severe infections in critically ill patients, there is still little understanding of dose optimization during the most important phase of the treatment, the initial phase. Disease-driven variations in pharmacokinetics and pharmacokinetics/ pharmacodynamics may compromise the therapeutic success of antibiotic therapy. Therefore, dose adjustments that account for these variations are paramount for improving antibiotic use in critically ill patients. Compelling evidence shows significant increases in the Vd of both hydrophilic and lipophilic drugs in critically ill patients as a consequence of patient pathology and from clinical interventions. These increases in the Vd can lead to lower than expected plasma concentrations during the first day of therapy, which may result in sub-optimal achievement of antibiotic pharmacokinetics/pharmacodynamic targets, resulting in inappropriate treatment. Therefore, loading doses of antibiotic during the first day of therapy that account for the predicted increase in the Vd are required. Further research towards the establishment of new dosing regimens that use loading doses to satisfy such increased volumes of distribution is recommended.

[Pharmacologic measures for the prevention of mechanical ventilation-associated pneumonia].

Ventilator associated pneumonia is the principal infectious complication in the Intensive Care Unit (ICU), and represents the main infectious cause of morbidity and mortality. Its diagnosis and management is complex. Consequently, its prevention becomes a cornerstone in daily clinical practice. Daily interruption of sedation, oral and digestive decontamination, prophylactic administration of systemic and/or inhaled antibiotics, glycemic control, stress ulcer prophylaxis, transfusion policy and timing and adequacy of antibiotic treatment are the main suggested pharmacologic interventions. The aim of this review is to critically describe the principal pharmacologic interventions for the prevention of ventilator associated pneumonia, focusing on the degree of the evidence and the appropriateness for daily clinical practice.

Optimizing antibiotic use in the intensive care unit.

Efforts directed at maximizing use of the existing antibiotic armamentarium are essential due to persisting increases in antibiotic resistance and the limited number of new antibiotics in development. The intensive care unit (ICU) is an especially complex environment deserving of specific focus. Antibiotic prescription in the ICU is difficult because of the presence of poorly susceptible pathogens, and the dynamic physiology of critically ill patients, which combine to alter bacterial-antibiotic interaction leading to suboptimal treatment of infections. The main objective of this article is to discuss the principles for optimization of antibiotic therapy, specifically focusing on altered pharmacokinetics in the critically ill patient, and the rationale for dosage adjustments. Optimizing antibiotic therapy involves early initiation of appropriate antibiotics, de-escalation where appropriate, minimization of duration of therapy, and avoidance of drug interactions. Furthermore, current opinion suggests that there remains significant capacity for improved antibiotic dosing in the ICU. Application of knowledge of the effect of pathophysiology on drug pharmacokinetics and dose adjustments that adhere to pharmacodynamic principles will facilitate improved antibiotic dosing in these “at risk” ICU patients.

Meropenem: Focus on its Use in Serious Bacterial Infections

Meropenem is an effective broad-spectrum carbapenem antibiotic frequently prescribed for treatment of severe bacterial infections. We conducted a structured review of the published literature to review the microbiology, clinical efficacy and pharmacokinetics, pharmacodynamics and tolerability of meropenem for the treatment of serious bacterial infections. Robust susceptibility data describes the broad spectrum of action of meropenem against many Gram positive and Gram negative organisms as well as stability against ESBL producing organisms. In clinical trials with other antibiotic comparators such as imipenem/cilastatin and cephalosporins (with and without an aminoglycoside), meropenem has been shown to have comparable efficacy for the treatment of different types of serious bacterial infections including severe community acquired pneumonia, complicated intra-abdominal infections, complicated skin and skin structure infections, bacterial meningitis and complicated urinary tract infections. In clinical studies of meropenem versus ceftazidime and an aminoglycoside, meropenem produced superior results for treatment of nosocomial and ventilator associated pneumonia. Meropenem also has a favourable pharmacokinetic profile enabling distribution into many tissue sites whilst maintaining a good safety and tolerability profile in adult and paediatric patients. Like other beta-lactam antibiotics, distribution into peripheral tissue may be impaired in critically ill patients. Administration can occur by either bolus dosing or intermittent infusion, although poor stability at room temperature complicates possible administration by continuous infusion. Such properties make meropenem a useful treatment for serious bacterial infections as either empiric or directed therapy, with administration by extended infusion appropriate for treatment of infections caused by pathogens with reduced susceptibility.

Medidas farmacológicas para la prevención de la neumonía asociada a la ventilación mecánica

Ventilator associated pneumonia is the principal infectious complication in the Intensive Care Unit (ICU), and represents the main infectious cause of morbidity and mortality. Its diagnosis and management is complex. Consequently, its prevention becomes a cornerstone in daily clinical practice. Daily interruption of sedation, oral and digestive decontamination, prophylactic administration of systemic and/or inhaled antibiotics, glycemic control, stress ulcer prophylaxis, transfusion policy and timing and adequacy of antibiotic treatment are the main suggested pharmacologic interventions. The aim of this review is to critically describe the principal pharmacologic interventions for the prevention of ventilator associated pneumonia, focusing on the degree of the evidence and the appropriateness for daily clinical practice.

Medidas farmacológicas para la prevencin de la neumonía asociada a la ventilación mecánica

Ventilator associated pneumonia is the principal infectious complication in the Intensive Care Unit (ICU), and represents the main infectious cause of morbidity and mortality. Its diagnosis and management is complex. Consequently, its prevention becomes a cornerstone in daily clinical practice. Daily interruption of sedation, oral and digestive decontamination, prophylactic administration of systemic and/or inhaled antibiotics, glycemic control, stress ulcer prophylaxis, transfusion policy and timing and adequacy of antibiotic treatment are the main suggested pharmacologic interventions. The aim of this review is to critically describe the principal pharmacologic interventions for the prevention of ventilator associated pneumonia, focusing on the degree of the evidence and the appropriateness for daily clinical practice.