Clinical efficacy of continuous infusion of piperacillin compared with intermittent dosing in septic critically ill patients

Since the bactericidal effects of beta-lactam antibiotics are time dependent, the optimum strategy for their administration could be continuous infusion. In this prospective, randomised controlled trial to evaluate the clinical efficacy of continuous infusion therapy, we evaluated the outcomes for 40 septic critically ill patients who received piperacillin either continuously (2 g intravenously (i.v.) over 0.5 h as a loading dose followed by 8 g i.v. daily over 24 h (n=20)) or as an intermittent infusion (3 g i.v. every 6h over 0.5 h (n=20)). Results from our study demonstrated that the clinical efficacy of piperacillin as a continuous infusion is superior to intermittent administration in critically ill patients. Change in APACHE II scores from baseline at the end of the second, third and fourth days, respectively, were 4.1, 5.1 and 5.2 for continuous infusion and 2.0, 2.6 and 2.8 for intermittent infusion (P< or =0.04). Considering minimum inhibitory concentrations (MICs) of 16 microg/mL and 32 microg/mL, the percentage of time for which piperacillin plasma concentrations were higher than the MIC (%T>MIC) was calculated for each patient in the two groups. For MICs of 16 microg/mL and 32 microg/mL, %T>MIC in the continuous infusion group was 100% and 65% of the dosing interval, respectively; in the intermittent infusion group, %T>MIC was only 62% and 39% of the dosing interval. There was a significant relationship between clinical results and laboratory data. It was shown that the superiority of the clinical efficacy of continuous infusion could be related to piperacillin pharmacodynamics. Continuous infusion significantly reduced the severity of illness as demonstrated by APACHE II scores during therapy.     

Population pharmacokinetics of continuous infusion of piperacillin in critically ill patients

Dosing recommendations for continuous infusion of piperacillin, a broad-spectrum beta-lactam antibiotic, are mainly guided by outputs from population pharmacokinetic models constructed with intermittent infusion data. However, the probability of target attainment in patients receiving piperacillin by continuous infusion may be overestimated when drug clearance estimates from population pharmacokinetic models based on intermittent infusion data are used, especially when higher doses (e.g. 16?g/24?h or more) are simulated. Therefore, the purpose of this study was to describe the population pharmacokinetics of piperacillin when infused continuously in critically ill patients. For this analysis, 270 plasma samples from 110 critically ill patients receiving piperacillin were available for population pharmacokinetic model building. A one-compartment model with linear clearance best described the concentration–time data. The mean?±?standard deviation parameter estimates were 8.38?±?9.91?L/h for drug clearance and 25.54?±?3.65?L for volume of distribution. Creatinine clearance improved the model fit and was supported for inclusion as a covariate. In critically ill patients with renal clearance higher than 90?mL/min/1.73?m², a high-dose continuous infusion of 24?g/24?h is insufficient to achieve adequate exposure (pharmacokinetic/pharmacodynamic target of 100% fT_{>4 x MIC}) against susceptible Pseudomonas aerginosa isolates (MIC ≤16?mg/L). These findings suggest that merely increasing the dose of piperacillin, even with continuous infusion, may not always result in adequate piperacillin exposure. This should be confirmed by evaluating piperacillin target attainment rates in critically ill patients exhibiting high renal clearance.     

First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis

The objectives of this study were (i) to compare the plasma concentration–time profiles for first-dose and steady-state piperacillin administered by intermittent or continuous dosing to critically ill patients with sepsis and (ii) to use population pharmacokinetics to perform Monte Carlo dosing simulations in order to assess the probability of target attainment (PTA) by minimum inhibitory concentration (MIC) for different piperacillin dosing regimens against bacterial pathogens commonly encountered in critical care units. Plasma samples were collected on Days 1 and 2 of therapy in 16 critically ill patients, with 8 patients receiving intermittent bolus dosing and 8 patients receiving continuous infusion of piperacillin (administered with tazobactam). A population pharmacokinetic model was developed using NONMEM^®, which found that a two-compartment population pharmacokinetic model best described the data. Total body weight was found to be correlated with drug clearance and was included in the final model. In addition, 2000 critically ill patients were simulated for pharmacodynamic evaluation of PTA by MIC [free (unbound) concentration maintained above the MIC for 50% of the dosing interval (50% f_T>MIC)] and it was found that continuous infusion maintained superior free piperacillin concentrations compared with bolus administration across the dosing interval. Dosing simulations showed that administration of 16 g/day by continuous infusion vs. bolus dosing (4 g every 6 h) provided superior achievement of the pharmacodynamic endpoint (PTA by MIC) at 93% and 53%, respectively. These data suggest that administration of piperacillin by continuous infusion, with a loading dose, both for first dose and for subsequent dosing achieves superior pharmacodynamic targets compared with conventional bolus dosing.     

Daily serum piperacillin monitoring is advisable in critically ill patients

The aim of the present study was to evaluate the benefit of monitoring serum piperacillin concentrations in critically ill patients. This was an 11-month, prospective, observational study in a 30-bed Intensive Care Unit in a teaching hospital, involving 24 critically ill patients with evidence of bacterial sepsis. All patients received a 66 mg/kg intravenous bolus of piperacillin in combination with tazobactam (ratio 1:0.125) followed by continuous infusion of 200 mg/kg/24 h. The dosage was adjusted when the serum piperacillin concentration either fell below 4× the drug's minimum inhibitory concentration (MIC) for the causative agent or exceeded the toxic threshold of 150 mg/L. With the initial regimen, serum piperacillin concentrations were within the therapeutic target range in only 50.0% of patients (n = 12). This proportion increased to 75.0% (18 patients) (P = 0.006) following dosage adjustment. For patients with low initial serum piperacillin concentrations (n = 8), the percentage of time during which the concentration remained above 4× MIC (%T > 4× MIC) was 7.1 ± 5.9% before dosage adjustment and 27.3 ± 8.6% afterwards. In conclusion, in critically ill patients, monitoring and adjustment of serum piperacillin levels is required to prevent overdosing and might also help to correct underdosing, an important cause of antibiotic therapy failure.     

Linezolid pharmacokinetic/pharmacodynamic profile in critically ill septic patients: intermittent versus continuous infusion

Pharmacokinetics and pharmacodynamics are significantly altered in critically ill septic patients and the risk of prolonged periods with concentrations below the minimum inhibitory concentration (MIC) and of low area under the serum concentration-time curve/MIC (AUC/MIC) ratios is of concern. We compared the pharmacokinetic/pharmacodynamic (PK/PD) profile of linezolid administered by intermittent or continuous infusion in critically ill septic patients. Patients were divided into two groups: intermittent infusion (Group I) (600mg/12h); or continuous infusion (Group C) (300mg intravenous loading dose +900mg continuous infusion on Day 1, followed by 1200mg/daily from Day 2). Linezolid serum levels were monitored for 72h and microbiological data were collected. The clinical outcome was monitored. Sixteen patients completed the study. MICs of susceptible pathogens were 2mg/L for 80% of the isolates. In Group I, linezolid trough serum levels (C(min)) varied widely and were below the susceptibility breakpoint (4mg/L) during the study period; in 50% of patients C(min) was <1mg/L. In Group C, mean linezolid serum levels were more stable and, starting from 6h, were significantly higher than C(min) levels observed in Group I and were always above the susceptibility breakpoint. Time that the free drug concentration was above the MIC (T(free)>MIC) of>85% was more frequent in Group C than in Group I (P<0.05). Finally, with continuous infusion it was possible to achieve AUC/MIC values of 80-120 more frequently than with intermittent infusion (P<0.05). According to PK/PD parameters, continuous infusion has theoretical advantages over intermittent infusion in this population of patients.     

Continuous infusion of beta-lactam antibiotics in severe infections: a review of its role

Continuous infusion of beta-lactam antibiotics has been widely promoted to optimise their time-dependent activity. Increasing evidence is emerging suggesting potential benefits in patient populations with altered pathophysiology, such as seriously ill patients. From a pharmacokinetic viewpoint, much information supports higher trough concentrations of beta-lactam antibiotics when administered by continuous infusion. This advantage of continuous infusion translates into a superior ability to achieve pharmacodynamic targets, particularly when the minimum inhibitory concentration (MIC) of the pathogen is >or=4 mg/L. One drawback of continuous infusion may be limited physicochemical stability. This issue exists particularly for carbapenem antibiotics whereby prolonged infusions (i.e. >3h) can be used to improve the time above the MIC compared with conventional bolus dosing. Few studies have examined clinical outcomes of bolus and continuous dosing of beta-lactam antibiotics in seriously ill patients. No statistically significant differences have been shown for: mortality; time to normalisation of leukocytosis or pyrexia; or duration of mechanical ventilation, intensive care unit stay or hospital stay. Some evidence suggests improved clinical cure and resolution of illness with continuous infusion in seriously ill patients. Pharmacoeconomic advantages of continuous infusion of beta-lactam antibiotics are well characterised. Available data suggest that seriously ill patients with severe infections requiring significant antibiotic courses (>or=4 days) may be the subgroup that will achieve better outcomes with continuous infusion.     

Pharmacokinetics of piperacillin-tazobactam: intermittent dosing versus continuous infusion

In the present study 24 hospitalized patients requiring empirical antibiotic treatment were randomly assigned to receive the beta-lactam antibiotic/beta-lactamase inhibitor combination piperacillin-tazobactam either as an intermittent or as a continuous infusion. According to pharmacokinetic modelling, the daily dose was reduced by 33% in patients receiving continuous infusion compared with intermittent infusion. Dose reduction because of impaired renal function was required in the intermittent dosing group for 5 of 12 patients compared with 1 of 12 patients in the continuous infusion group. However, the mean daily dose in the continuous group was 15% less than the intermittent infusion group. Mean serum concentrations of piperacillin were to 39.0 microg/ml after the end of bolus distribution, exceeding by far the minimal inhibitory concentration of the most clinically relevant pathogens. The corresponding mean value for tazobactam was 6.3 microg/ml. Pharmacokinetic/pharmacodynamic modelling suggests that both treatment schemes should produce virtually identical anti-infective responses to sensitive, intermediate and resistant strains. In the present study the continuous infusion of piperacillin/tazobactam provided adequate antibacterial activity over the 24-h dosing period and offers the potential for a substantial reduction in the total daily dose.     

Pharmacokinetics of Aztreonam and Imipenem in Critically Ill Patients with Pneumonia

Study Objective . To evaluate the pharmacokinetic profiles of aztreonam and imipenem in critically ill trauma patients with pneumonia. Methods . Trauma patients in intensive care units who were intubated within 3 days of hospital admission were eligible for the study. Patients with the clinical diagnosis of pneumonia were consecutively randomized to receive either aztreonam plus vancomycin or imipenem-cilastatin. Serial blood samples were taken and sputum was collected to determine aztreonam and imipenem concentrations after 2–3 days and 7–8 days of therapy. Pharmacokinetics of both agents were estimated and compared with estimates from healthy volunteers. Results . Twenty patients were enrolled in the study, 10 patients received imipenem-cilastatin, and 10 received aztreonam plus vancomycin. Steady-state volume of distribution (V_ss) for aztreonam at 2–3 days and 7–8 days was significantly greater in patients than in historical controls, whereas the V_ss for imipenem was greater at 2–3 days. The β-half-life for aztreonam at both sampling periods was significantly greater in patients than in controls. No significant changes in pharmacokinetics occurred over time for either antibiotic. Sputum concentrations of aztreonam and imipenem were highly variable when sampled 2 hours after the infusion. Conclusion . Larger volumes of distribution were observed for both aztreonam and imipenem in trauma patients than in volunteers, suggesting that standard initial dosages of the antibiotics may result in lower concentrations in these critically ill patients. Both antibiotics penetrated into the sputum of most patients; however, the degree of penetration was highly variable in relation to serum concentrations.     

Penetration of piperacillin and tazobactam into pneumonic human lung tissue measured by in vivo microdialysis

OBJECTIVES: The pharmacokinetic profile of antibiotics at the site of anti-infective action is one of the most important determinants of drug response, since it correlates with antimicrobial effect. Up to now, only limited information on the lung tissue pharmacokinetics of antibiotic agents has been available. The aim of this study was to measure, using a new microdialysis-based approach, antibiotic penetration into the extracellular space fluid of pneumonic human lung parenchyma. PATIENTS AND METHODS: The lung penetration of a combination of piperacillin and tazobactam, substances with low protein binding, was determined in five patients suffering from pneumonia and metapneumonic pleural empyema. The condition was treated by decortication after lateral thoracotomy. Intra-, or post-operatively, respectively, two microdialysis probes were inserted into pneumonic lung tissue, and into healthy skeletal muscle to obtain reference values. Serum and microdialysis samples were collected at 20-min intervals for at last 8 h following i.v. administration of a single dose of 4 g piperacillin and 500 mg tazobactam. RESULTS: The mean free interstitial concentration profiles of piperacillin in infected lung tissue and serum showed a maximal tissue concentration (Cmax) of 176.0 +/- 105.0 mg l-1 and 326.0 +/- 60.6 mg l-1, respectively. The mean AUC (area under the curve) for infected lung tissue was 288.0 +/- 167.0 mg.h l-1 and for serum 470.0 +/- 142.0 mg.h l-1. There was a statistically significant difference between AUC (lung) and AUC (serum) (P = 0.018) as well as between AUC (lung) and AUC (muscle) (P = 0.043). The intrapulmonary concentrations of piperacillin and tazobactam exceeded the minimum inhibitory concentrations (MIC) for most relevant bacteria for 4-6 h. The procedure was well tolerated by all patients and no adverse events or microdialysis-associated side-effects were observed. CONCLUSION: This microdialysis technique enabled continuous tissue pharmacokinetic measurement of free, unbound anti-infective agents in the lung tissue of patients with pneumonia. The present data corroborate the use of piperacillin and tazobactam in the treatment of lung infections caused by extracellular bacteria and demonstrate the distribution of piperacillin and tazobactam in the interstitial space of pneumonic lung tissue.     

Does consistent piperacillin dosing result in consistent therapeutic concentrations in critically ill patients? A longitudinal study over an entire antibiotic course

Piperacillin plasma concentrations are known to vary between critically ill patients. However, there are no comprehensive data on the variability of antibiotic concentrations within the same patient. The purpose of this study was to investigate the adequacy of dosing during an entire 7-day antibiotic course and to investigate the variability in antibiotic trough concentrations both between patients and within the same patient. Piperacillin trough concentrations were measured daily in critically ill patients with normal renal function. The drug assay was performed using UPLC–MS/MS. The pharmacokinetic/pharmacodynamic target was 100% fT_>MIC of the Pseudomonas aeruginosa EUCAST breakpoint. Within- and between-patient variability were calculated as percent coefficient of variation (CV). Eleven patients treated for pneumonia were included in this nested prospective observational cohort study. The median (range) age was 67 (18–79) years, weight was 75 (57–90) kg and BMI was 23.5 (22.3–26.4). The median (range) creatinine clearance on Day 1 of antibiotic treatment was 102 (62–154) mL/min. Trough concentrations were variable, ranging from 4.9 mg/L to 98.0 mg/L. A median CV of 40% for within-patient variability and 57% for between-patient variability was found. Within-patient variability was inversely correlated with SOFA score (R = 0.65, P = 0.027) and APACHE II score on admission (R = 0.73, P = 0.009). In conclusion, piperacillin concentrations varied widely both between patients and within the same patient. Within-patient variability was inversely correlated with disease severity. Consistent dosing of piperacillin/tazobactam does not result in consistent piperacillin concentrations throughout the entire treatment period.     

A higher dose of vancomycin in continuous infusion is needed in critically ill patients

Compared with intermittent infusion, continuous infusion of vancomycin is cheaper and logistically more convenient, achieves target concentrations faster, results in less variability in serum vancomycin concentrations, requires less therapeutic drug monitoring and causes less nephrotoxicity. Given that critically ill patients may develop very large volumes of distribution as well as supranormal drug clearance, in this study it was shown, despite the limited number of patients studied, that to achieve a target plateau concentration of 25mg/L a daily dose of 3000 mg of vancomycin in continuous infusion is needed following an appropriate loading dose.     

β-Lactam pharmacokinetics and pharmacodynamics in critically ill patients and strategies for dose optimization: a structured review

1. Infections and related sepsis are two of the most prevalent issues in the care of critically ill patients, with mortality as high as 70%. Appropriate antibiotic selection, as well as adequate dosing, is important to improve the clinical outcome for these patients. 2. β-Lactams are the most common antibiotic class used in critically ill sepsis patients because of their broad spectrum of activity and high tolerability. β-Lactams exhibit time-dependent antibacterial activity. Therefore, concentrations need to be maintained above the minimum inhibitory concentration (MIC) of pathogenic bacteria. β-Lactams are hydrophilic antibiotics with small distribution volumes similar to extracellular water and are predominantly excreted through the renal system. 3. Critically ill patients experience a myriad of physiological changes that result in changes in the pharmacokinetics (PK) of hydrophilic drugs such as β-lactams. A different approach to dosing with β-lactams may increase the likelihood of positive outcomes considering the pharmacodynamics (PD) of β-lactams, as well as the changes in PK in critically ill patients. 4. The present review describes the strategies for dose optimization of β-lactams in critically ill patients in line with the PK and PD of these drugs.     

Pharmacokinetics of linezolid in critically ill patients

Introduction: Linezolid is an oxazolidinone antibiotic active against Gram-positive bacteria, and is most commonly used to treat life-threatening infections in critically ill patients. The pharmacokinetics of linezolid are profoundly altered in critically ill patients, partly due to decreased function of vital organs, and partly because life-sustaining drugs and devices may change the extent of its excretion.

Areas covered: This article is summarizes key changes in the pharmacokinetics of linezolid in critically ill patients. The changes summarized are clinically relevant and may serve as rationale for dosing recommendations in this particular population.

Expert opinion: While absorption and penetration of linezolid to tissues are not significantly changed in critically ill patients, protein binding of linezolid is decreased, volume of distribution increased, and metabolism may be inhibited leading to non-linear kinetics of elimination; these changes are responsible for high inter-individual variability of linezolid plasma concentrations, which requires therapeutic plasma monitoring and choice of continuous venous infusion as the administration method. Acute renal or liver failure decrease clearance of linezolid, but renal replacement therapy is capable of restoring clearance back to normal, obviating the need for dosage adjustment. More population pharmacokinetic studies are necessary which will identify and quantify the influence of various factors on clearance and plasma concentrations of linezolid in critically ill patients.     

The relevance of drug clearance to antibiotic dosing in critically ill patients

To maximise the effect of an antibiotic it is necessary to pay careful attention to dosing. The maintenance dose is determined by antibiotic clearance which is usually determined in young healthy adults with normal physiology. Antibiotic clearance in critically ill patients may increase or decrease due to altered physiology and the treatments that are administered. Clearance may also vary significantly over time in patients with critical illness. Advancing age and comorbidities, in particular chronic kidney disease, can also decrease antibiotic clearance. Therefore, it is complicated and arguably impossible to suggest generic guidelines for the dosing of antibiotics in critically ill patients. Factors that influence clearance must be identified and accounted for in each patient for a rational approach to dose adjustment of antibiotics in patients with critical illness. The necessary changes can be predicted by understanding pharmacokinetic concepts. It is necessary to quantify organ function in patients at multiple time points because this can be used to estimate antibiotic clearance and guide dose selection. For example, creatinine clearance should be calculated but methods used in ambulatory patients may not apply to patients with critical illness. If possible, therapeutic drug monitoring should be conducted to ensure that antibiotic concentration targets are achieved and also to guide titration of subsequent doses. If blood sampling is carefully planned it may be possible to directly measure antibiotic clearance for dose adjustment. The purpose of this article is to review the concept of clearance and to highlight circumstances where antibiotic clearance may be altered in patients with critical illness. Strategies for dose modification of antibiotics in critically ill patients will be discussed.     

Influence of the mode of intravenous administration on the penetration of ceftazidime into tissues and pleural exudate of rats.

The influence of the mode of intravenous (i.v.) administration (bolus injection or continuous infusion) on the tissue penetration of ceftazidime was studied in the rat. The antibiotic concentration was monitored in serum, pleural exudate, vitreous humor, kidney, liver, lung, testicles and epididymal fat tissue. Administration as a bolus resulted in a significantly higher AUC in pleural exudate and in higher peak levels in serum, liver and lung than continuous infusion, which produced a higher peak concentration in kidney than a bolus. No differences in AUC and peak concentrations between the two methods of administration were observed in the other tissues or fluids. With either method of administration the highest antibiotic accumulation was observed in kidney.     

Intravenous to oral antibiotic switch therapy

I.v.-to-p.o. switch therapy has become the mainstay of antibiotic therapy for the majority of patients. I.v.-to-p.o. switch therapy is inappropriate for critically ill patients who require i.v. antibiotic therapy and should not be considered in patients who have the inability to absorb drugs. These exceptions constitute a very small percentage of hospitalized patients for which i.v.-to-p.o. switch therapy is ideal. I.v.-to-p.o. switch therapy is best achieved with antibiotics that have high bioavailability that result in the same blood and tissue concentrations of antibiotic as their intravenous counterpart and have few gastrointestinal side effects. Antibiotics ideal for i.v.-to-p.o. switch programs include chloramphenicol, clindamycin, metronidazole, TMP-SMX, fluconazole, itraconazole, voriconazole, doxycycline, minocycline, levofloxacin, gatifloxacin, moxifloxacin and linezolid. Antibiotics that may be used in i.v.-to-p.o. switch programs that have lower bioavailability but are effective include beta-lactams and macrolides. For antibiotics with no oral formulation, e.g., carbapenems, equivalent coverage must be provided with an oral antibiotic from an unrelated class. Excluding gastrointestinal malabsorptive disorders, disease state is not a determinant of suitability for i.v.-to-p.o. switch programs. I.v.-to-p.o. switch programs should be used in patients with any infectious disease disorder for which there is effective oral therapy and is not limited to certain infectious diseases. Oral absorption of antibiotics is near normal in all but the most critically ill patients. Therefore, even in sick, hospitalized individuals, p.o. therapy is appropriate. I.v-to-p.o. switch therapy has several important advantages including decreasing drug cost (i.v. vs. p.o.), decreasing length of stay permitting earlier discharge and optimal reimbursement and decreasing or eliminating i.v. line phlebitis and sepsis with its cost implications. Clinicians should consider all patients, except the most critically ill or those unable to absorb oral medications, as candidates for treatment for most or all of their antibiotic treatment with oral antibiotics. (c) 2001 Prous Science. All rights reserved.     

Pharmacodynamics of piperacillin in severely ill patients evaluated by using a PK/PD model

Penetration of antiinfective drugs into soft tissues is essential for antimicrobial killing at the target site, but is substantially lower in severely ill patients compared with healthy subjects. The present study was conducted to assess the antimicrobial effect of piperacillin in severely ill patients. Strains of Staphylococcus aureus and Pseudomonas aeruginosa were exposed in vitro to concentrations of piperacillin, simulating the pharmacokinetic profiles measured in soft tissue of patients and healthy subjects. The simulation for patients resulted in effective killing, whereas bacterial regrowth was detected for healthy subjects. Our in vitro simulation showed that bacterial killing may be effective in severely ill patients despite relatively low concentrations of piperacillin at the target site. This finding is due to impaired renal function and subsequently prolonged tissue and plasma half-lives of piperacillin in intensive care patients.     

Pulse dosing versus continuous infusion of antibiotics. Pharmacokinetic-pharmacodynamic considerations

The issue of whether it is better to administer antibiotics as an intermittent bolus dose or a continuous intravenous infusion has been debated for several decades. This paper reviews the extensive literature on the topic, considering both the pharmacokinetic and pharmacodynamic aspects of antibacterials as well as experimental results from studies conducted in vitro, in animals and in humans. It is evident from reviewing the literature that neither mode of administration is clearly superior to the other. The decision regarding the mode of administration must take into account the antibiotic being used, the bacteria, the patient and the infection, as well as the pharmacokinetics of the particular drug in the individual patient. The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) are useful indicators of the relative in vitro effectiveness of antibiotics, but it is not clear what relevance these parameters have to the desired antibiotic concentrations in vivo. Furthermore, questions of serum vs tissue fluid concentrations, peak concentrations vs AUC, and free vs total concentration are all important issues to consider in assessing the optimal mode of administration. The importance of newer indices such as the post-antibiotic effect are now beginning to be recognised. A number of scientists are actively engaged in developing a system to identify the most appropriate mode of administration based upon the integration of an antibiotic's pharmacodynamics and pharmacokinetics. Within the next few years we anticipate that appropriate guidelines should have been developed to aid the optimisation of parenteral administration, at least for some antibiotics.     

How to measure pharmacokinetics in critically ill patients?

There is pressing need to better understand pharmacokinetics in critically ill patients. This will aid clinicians in selecting optimal dosing regimens. Pharmacokinetic studies are difficult in this population due to the heterogeneity of the patients and the practical issues of research involving critically ill patients. Therapeutic drug monitoring is routinely performed to guide dosing for aminoglycoside and glycopeptide antibiotics. Expanding its use to other drug classes could provide new therapeutic advantages. Plasma concentration may not always reflect tissue distribution in critically ill patients. Microdialysis is a technique that can be applied in the Intensive Care Unit to measure tissue concentrations and provide further insights to antimicrobial therapy for critically ill patients. Finally, the application of population pharmacokinetic analysis in studies in critically ill patients may identify factors affecting pharmacokinetics and enhance drug dosing regimens for varied patient groups.     

Microdialysis for in vivo pharmacokinetic/pharmacodynamic characterization of anti-infective drugs

Inadequate tissue penetration of antibiotics can lead to therapeutic failure and bacterial resistance. Pharmacokinetic evaluation of antibiotics should therefore be based on tissue rather than serum concentrations. Over several years, tissue concentration data obtained by methods such as tissue biopsies have flawed the correct interpretation of antibiotic tissue distribution. Microdialysis--a semi-invasive catheter-based sampling technique--has been employed for the in vivo measurement of antibiotic tissue pharmacokinetics. Owing to selective access to the target site for most anti-infective drugs, microdialysis satisfies regulatory requirements for pharmacokinetic distribution studies and might become a reference technique for tissue distribution studies in the near future. Furthermore, microdialysis might contribute to the definition of meaningful surrogate markers for antibiotic efficiency during drug development.