Pharmacokinetic/pharmacodynamic indices: are we ready to use them in daily practice?

Prescribing antimicrobial treatment should not be considered an action that is performed routinely. The use of antibiotics should be accompanied by in-depth reflection, both at the time of drug selection and of administration, in order to achieve maximum therapeutic success, minimize drug toxicity and decrease the potential impact on bacterial resistance. Currently, there are multiple experiences published that have related the inappropriate use of antimicrobial agents to an increase in mortality, particularly in patients with severe infections in which particular species of pathogens are involved.

With the purpose of optimizing the use of antimicrobials, it has been proposed that antibiotic treatment should be viewed from an overall perspective, as opposed to obsolete considerations that focus on the selection of the more potent molecules predominantly based on in vitro characteristics to guarantee the success of antimicrobial therapy. In this line, Pea and Viale have introduced the idea that antibiotic treatment should always be accompanied by the consideration of a series of important variables, including the antibiotic agent prescribed for treating the infection, the site of infection, the isolated pathogen, the MIC of the prescribed agent and, finally, the patient’s pathophysiology, which increases in parallel with severity of illness [1]. Additionally, physicochemical properties of antibiotics play an essential role in the treatment of infections: the hydrophilic or lipophilic behavior of these molecules determines their ability to cross different barriers, their activity against intracellular or extracellular microorganisms, their hepatic or renal clearance and their higher or lower distribution volume, which is a crucial aspect in critically ill patients.

The term ‘pharmacodynamics’ refers to the relationship between the amount of drug present in the plasma, tissues or other biological fluids and the activity and toxic effects of the drug. In the antimicrobial therapeutic field, pharmacodynamics has the main objective of studying the relationships between concentrations reached by antibiotics and effects obtained. According to this concept and the different behavior of antibiotic classes against pathogens to which they are directed, different pharmacokinetic/pharmacodynamic (PK/PD) indices are developed. It should be noted that the intention to achieve high concentrations of some antibiotics at the site of infection is not always associated with a higher bactericidal effect. This is the case for some antibiotic families, mainly those included in the group of β-lactams, in which bactericidal activity is reached with concentrations that multiply the MIC value against the pathogen responsible for infection by only a small number [2]. The time above the MIC; that is, the time during which plasma drug concentration exceeds the MIC value for a particular pathogen, is the PK/PD index, which enables a better assessment of the antimicrobial activity of β-lactams [3]. In this case, better therapeutic results are obtained with the use of lower doses that are administered more frequently. To optimize the activity of this antibiotic family, the possible benefits of continuous infusion compared with the standard practice of intermittent infusion has been considered. However, in most studies the benefits of this strategy have been restricted to demonstrating that it allows optimization of economic resources; however, benefits from a clinical point of view have rarely been observed. Nevertheless, a recent study with more a sophisticated design and statistical analysis has demonstrated that there are probably some intrinsic patient factors; primarily, the severity of illness present at the time of infection, which may be closely related to the beneficial effects of the use of some β-lactams in continuous infusion, particularly a lower mortality with piperacillin–tazobactam administered following this regimen to patients with an Acute Physiology and Chronic Health Evaluation (APACHE) II score higher than 17 [4]. However, this observation must be confirmed by future studies.

For other antibiotic families, such as aminoglycosides or quinolones in which antimicrobial bactericidal activity depends on the concentration reached, the PK/PD indexes that are predictors of therapeutic success are the AUC:MIC ratio or ratio of peak concentration and MIC (C_max:MIC). C_max:MIC is especially useful for aminoglycosides [5]. The AUC_24h:MIC ratio relates to the steady state AUC value and MIC. This parameter is especially applicable as a predictor of efficacy, such as in the case of fluoroquinolones. Another PK/PD index similar to AUC:MIC is the area under the inhibitory curve (AUIC), which may be calculated from the AUC for the time period over 24 h where the concentration exceeds the MIC (AUC > MIC:MIC over 24 h). Although AUIC may be a valuable parameter in particular cases, the AUC:MIC ratio is more generally used because it is easy to calculate and is independent of whether or not antibiotic concentrations exceed the MIC for a particular microorganism.

In the case of β-lactams, the available literature on well-designed studies in humans relating plasma concentrations of glycopeptides with pharmacodynamic parameters is very limited. At the present time, it is considered that monitoring plasma vancomycin levels may be very useful in the management of severe infections. Based on an overestimation of vancomycin nephrotoxicity, optimal minimal concentrations (C_min) of 10 mg/l have been proposed. Currently, it is recommended to use sufficient doses of vancomycin to achieve C_min between 15 and 20 mg/l, or even higher in the case of infections of the CNS [6]. The selection of the best PK/PD index as a predictor of clinical efficacy for vancomycin is a matter of controversy. In this respect, studies using the C_max:MIC ratio as the reference have been performed, whereas the current trend is to use AUC:MIC. On the other hand, a strategy that is being extended in clinical practice, in particular in the care of critically ill patients, is the administration of vancomycin in continuous infusion, which has been related to a lower toxicity and more rapid achievement of therapeutic plasma concentrations. However, sufficient evidence in terms of clinical results of the higher superiority of this form of administration compared with the standard use is lacking.

In the PK/PD area, different models have shown the advantages of obtaining certain values for PK/PD indices, based on experimental models in which plasma concentrations of the drug are analyzed. However, the results of these studies are not applicable to all types of infection, particularly when penetration of the antibiotic agent is affected by the ability to cross different physiological barriers, the presence of biological fluids, pH modification or physiopathological changes that are produced in some patients.

In other cases, mainly in treatment with aminoglycosides, it should be remembered that the objective of achieving sufficient concentrations to maintain optimal PK/PD indices is highly limited when renal elimination of the drug is impaired owing to renal failure or excessive drug clearance (a common occurrence in clinical practice). A recent study demonstrated that incorrect monitoring and excessive prolongation of treatment were the main factors involved in the inappropriate use of aminoglycosides [7]. Even in the case of β-lactams, it has been proposed that the selection of a particular PK/PD index as a predictor of therapeutic success may be compromised by the duration of antibiotic treatment [8].

In clinical practice, the application of the aforementioned PK/PD concepts require a series of conditions and resources that can be summarized as follows [9,101]:

•	Analytical conditions: it is necessary to have available accurate, precise and specific laboratory techniques, providing results rapidly and with a reasonable cost. To guarantee these requirements, validation of the procedure is necessary. Moreover, the laboratory involved in drug monitoring should adhere to some form of external quality program to confirm the reliability of the results obtained;
•	Pharmacological conditions: it is necessary to define serum concentrations of antibiotics related to either the efficacy or toxicity. This therapeutic margin is the expression of a concentration–effect profile for a particular population, rather than for a given patient. For this reason, drug clearance and distribution volumes should be known, as well as factors that may affect intra- and interindividual pharmacokinetic variability;
•	Clinical conditions: laboratory data should be interpreted according to type and site of infection, the patient’s immune status, concomitant pharmacological treatments, comorbidities and systemic response to infection. In critically ill patients, other factors to consider include the high frequency of multiorgan dysfunction, mechanical ventilation, the use of drugs that increase clearance of antibiotics (diuretics or inotropic agents) and the resistance profile of causative pathogens. In these circumstances, PK/PD parameters should be applied individually;
•	Informatics conditions: after monitoring of serum antibiotic concentrations, the use of computer programs is a common resource in clinical decision making. There are different, nonstandardized programs that should be unified for a common application in the hospital setting. General requirements include easy access and handling, rapid execution, the possibility to provide clinical reports and to store and update information, as well as the capacity to integrate different databases of drugs, patients or populations;
•	Pharmacoeconomic conditions: development of drug monitoring is conditioned by economical benefits that may result from its implementation. Therefore, pharmacoeconomic studies showing that individualized pharmacokinetic dosing is a cost-effective practice compared with other dosing systems are necessary. In this respect, knowledge of the cost of therapeutic failures by inappropriate dosing, adverse effects caused by the misuse of antibiotics, treatments and additional tests, or increasing the length of hospital stay, should be included in studies designed to assess daily clinical applicability of PK/PD parameters.

In recent years, research on the PK/PD relationships has markedly advanced. The introduction of concepts with the mutant-selection window may be very useful in the near future for the study of bacterial resistance. Moreover, the introduction of mathematical models, such as Monte Carlo simulation, allows optimal combination of PK/PD data with the aim to predict therapeutic results of particular dosing schedules. In addition, the pharmaceutical industry has assumed the importance of developments in this field, so that pharmacokinetic data and optimal PK/PD indices for most molecules introduced recently into the market, and those in the last steps of development, are currently available. However, despite these impressive advances, basic laboratory techniques for the monitoring of antibiotic plasma concentrations are not available in many hospitals. This problem is further accentuated when required techniques for the assessment of plasma drug concentrations are more complicated, such as the use of high-pressure liquid chromatography, among others. In these cases, qualified personnel and more resources are needed. With the lack of knowledge of optimal values of PK/PD indices in infections localized at sites of difficult access, such as bone or CNS infections, we still have a considerable amount to learn.

Acknowledgements

We thank Marta Pulido for editorial assistance.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.