Class-dependent relevance of tissue distribution in the interpretation of anti-infective pharmacokinetic/pharmacodynamic indices

Abstract

The pharmacokinetic/pharmacodynamic (PK/PD) indices useful for predicting antimicrobial clinical efficacy are well established. The most common indices include the time free drug concentration in plasma is above the minimum inhibitory concentration (MIC) (fT_>MIC) expressed as a percent of the dosing interval, the ratio of maximum concentration to MIC (C_max/MIC), and the ratio of the area under the 24-h concentration–time curve to MIC (AUC_0–24/MIC). A single PK/PD index may correlate well with an entire antimicrobial class. For example, the β-lactams correlate well with the fT_>MIC. However, other classes may be more complex and a single index cannot be generalised to the class, e.g. the macrolides. The rationale behind which PK/PD index best correlates with efficacy depends on several factors, including the mechanism of action, the microbial kill kinetics, the degree of protein binding and the degree of tissue distribution. Studies have traditionally emphasised the first two factors, whilst the significance of protein binding and tissue distribution is increasingly appreciated. In fact, the latter two factors may partially elucidate why the magnitude of reported target indices are not always as expected. For example, tigecycline and telithromycin are clinically efficacious with average serum concentrations below their MICs over a 24-h period. Therefore, to understand more fully the PK/PD relationship of antibiotics and to better predict the clinical efficacy of antibiotic dosing regimens, assessment of free drug concentrations at the site of action is warranted.

Introduction

Pharmacokinetic/pharmacodynamic (PK/PD) characterisation of antimicrobial agents has allowed a better understanding of why a particular dosing regimen achieves clinical success or failure. Using techniques first pioneered by Eagle et al. [1], [2] and further developed by Craig and co-workers [3], [4], [5], dose selection has become a much more sophisticated process over previous empirical methods. In vitro and in vivo experiments are used to define a relationship between drug concentration (pharmacokinetics) and effect (pharmacodynamics) and allow for a clear target to be identified so that efficacy is achieved in the clinical setting [6]. The PK/PD indices typically used for antimicrobials include the time the free drug concentration remains above the minimum inhibitory concentration (MIC) (fT_>MIC) expressed as a percent of the dosing interval, the ratio of the maximum concentration and MIC (C_max/MIC), and the ratio of the 24-h area under the concentration–time curve and MIC (AUC_0–24/MIC) [3]. In vivo PK parameters are usually determined from serum or plasma drug profiles, whilst in vitro PD parameters commonly use culture media drug concentrations.

The index that best correlates with a particular antibiotic depends on several factors. One of these factors is the pattern of microbial kill exhibited by the compound, which is frequently referred to as either time-dependent killing or concentration-dependent killing. Antibiotics that display time-dependent killing typically reach a maximum effect at a concentration ca. 4× MIC [7], [8]. Once this maximum effect is reached, increasing the concentration does not increase the rate of bacterial death, as shown for ticarcillin in Fig. 1[7]. Antibiotics that display concentration-dependent killing produce an increasing effect as the concentration increases, as shown for tobramycin and ciprofloxacin in Fig. 1. However, categorising an agent's antimicrobial activity as time- or concentration-dependent is not always obvious, as shown in Fig. 2 where profiles for concentrations >4× MIC appear similar for all compounds [9].

Concentration-dependent antibiotics usually correlate efficacy with exposure and the MIC, i.e. the C_max/MIC or the AUC_0–24/MIC. The efficacy of time-dependent antimicrobials usually depends on fT_>MIC as a percentage of the dosing interval. However, time-dependent antibiotics that display a prolonged post-antibiotic effect (PAE), i.e. the persistence of activity after removal of the drug or after concentrations drop below the MIC [10], [11], [12], often correlate well with the AUC_0–24/MIC. Although the mechanisms of the PAE have been speculated, the PAE appears to depend on the drug, the pathogen and the infection model [10]. The term PAE is used collectively to explain residual effects of complex PK and PD processes that are not well defined.

Other factors that influence the significance of PK/PD indices for predicting clinical efficacy that are often overlooked include protein binding and tissue distribution. Recently, it has been stressed that only free concentrations should be taken into account in these indices as only free drug has the ability to exhibit a pharmacological effect [13], [14], [15]. Similarly, it follows that the most relevant concentration for antibiotic efficacy would be the concentration within the interstitial space fluid (ISF) of target tissues, as most infections are located outside the plasma or serum where drug concentrations are commonly monitored. The volume of distribution, and subsequently the degree of tissue distribution, varies greatly between antimicrobial classes, as shown in Table 1[16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. It is the goal of this paper to review the PK/PD relationship of various antimicrobial classes and to analyse this relationship by examining the mechanism of action, in vitro kill kinetics and free tissue concentrations. Additionally, the PAE will be discussed in some instances, as it may be used to account for additional uncharacterised PD effects.