Macrolides: pharmacokinetics and pharmacodynamics

https://doi.org/10.1016/S0924-8579(01)00406-XGet rights and content

Abstract

Three pharmacokinetic/pharmacodynamic parameters—(i) the peak concentration to the minimum inhibitory concentration ratio (Cmax/MIC); (ii) the area under the concentration–time curve to MIC ratio (AUC24h/MIC); and (iii) the time the concentration exceeds the MIC (T>MIC)—are important predictors of the clinical efficacy of antibiotics. For antibiotics with pronounced concentration-dependent killing, such as the fluoroquinolones or the aminoglycosides, Cmax/MIC and AUC24/MIC are the main factors that establish efficacy. Antibiotics with a weak, or no, concentration dependency generally have their efficacy linked to T>MIC, and these include the β-lactams and the conventional macrolides. Antibiotics with weak concentration-dependent effects, but with prolonged persistent effects, such as tetracyclines and azithromycin, have their activity mostly related to the AUC24/MIC. By applying these concepts to current antibiotics, and also to the development of novel agents, it is possible to optimise their dosages and administration schedules. This will maximise therapeutic efficacy, may prevent or delay the emergence of bacterial resistance to antibiotics, and can certainly minimise side-effects.

Introduction

Determination of the optimal dosing for antibiotics has clinical cure as its aim. Development of effective antibiotic treatment commences with the consideration of the basic chemistry of antibiotic molecules, continues with the evaluation of their microbiological activity (including bactericidal activity and spectrum of activity) and, through understanding of their pharmacokinetic (PK) and pharmacodynamic (PD) properties and application of the corresponding concepts, culminates in proven therapeutic effectiveness.

PK/PD are key in facilitating the translation of microbiological activity into clinical situations and to ensuring that the antibiotic achieves a successful outcome. Dosing regimens for antibiotics have not always been the most appropriate. For example, aminoglycosides have been dosed three times daily for many years, but we now know that this schedule was far from being optimal [1], [2]. Conversely, the macrolides with relatively short half-lives have been often considered for twice- or even once-daily administration. Even a twice-daily dosing regimen has been suggested for fourth-generation cephalosporins, even though these drugs have very short half-lives and are, as we shall see, time-dependent [3], [4]. In very general terms, PK/PD aims at avoiding these mistakes by determining, as early on as possible during the drug development process what is the optimal dosage and schedule of administration for the antibiotic under study.

PK/PD has often been considered as a ‘black box’, the intricacies of which could only be understood by highly specialised scientists and were of little interest to the clinician. However, beyond the esoterics of mathematical formulae and the corresponding analyses, the ‘black box’ of PK/PD is nothing more than trying to understand how the peak plasma concentration of a drug (Cmax), its area under the plasma concentration–time curve (AUC24h) and, in case of an antibiotic, its MIC relate to its clinical activity and toxicity (Fig. 1). In that sense, PK/PD is simply putting PK to work for what should be its aim, namely allowing for an efficient therapy.

Section snippets

PK/PD: efficacy and safety

A critical point in antibiotic therapy is to balance the serum antibiotic concentrations, which vary over time, in order to achieve optimal bacterial eradication and minimal side-effects [5]. In vitro modelling, properly designed animal model experiments and PK information collected from clinical trials should, if combined and assessed globally, provide us with information about the characteristics of an antibiotic that are essential for therapeutic efficacy, and may be able to predict toxicity

Concentration-dependent versus concentration-independent bacterial killing

Research undertaken over the last 15 years has allowed us to define the key PK/PD properties of the main classes of antibiotics that need to be taken into account for optimising their efficacy [5], [10], [11], [12], [13], [14], [15].

For a large series of antibiotics (e.g. aminoglycosides, fluoroquinolones, metronidazole, daptomycin, ketolides and amphotericin), the Cmax/MIC and the AUC24h/MIC ratios clearly play the most important roles (Table 1), probably because these drugs have a marked

Bacterial kill kinetics and prolongation of effect

Another matter of importance in antibiotic action is the speed of bacterial killing. Aminoglycosides and fluoroquinolones are rapidly bactericidal. By contrast, β-lactams, vancomycin, macrolides, oxazolidinones, clindamycin, tetracyclines and flucytosine exhibit considerably slower killing. This makes it all the more necessary to optimise the time of exposure of the offending organism to these antibiotics [15].

Besides the direct effect of antimicrobial agents on bacteria, some classes of drugs

Achieving appropriate values for PK/PD parameters

Having determined which parameter is important for a given antibiotic in determining clinical efficacy, the question naturally arises as how to obtain it. Considering first the Cmax/MIC ratio, it is clear that this value will be directly dependent on the dose and inversely related to the volume of distribution. Taking aminoglycosides as an example, it becomes clear that the initial dose will be the critical point to take into consideration, which in itself explains the importance of the

Intracellular activity of antibiotics

Some bacteria (e.g. Legionella and Chlamydia species) are found within subcellular compartments, such as the phagosomes (Fig. 4). Others, such as Staphylococcus aureus, Salmonella species and Mycobacterium leprae, are mostly located within phagolysosomes. Some bacteria, including Listeria and Shigella, are detected in the cytosol because they are able to escape very quickly from phagosomes. Infections caused by these organisms are often difficult to treat, and the causative organism is rarely

Pharmacokinetics and bacterial resistance

If antibiotics do not effectively and quickly kill bacteria, there is a possibility of selection of less sensitive subpopulations or, worse, of bacteria that have either become resistant by mutation or have acquired resistance mechanisms (often from the commensal flora). This can result in clinically meaningful failures. Macrolides, in general, are not bactericidal, but emergence of resistance has not been for long as critical an issue as it has been for fluoroquinolones. Yet, the situation has

The optimal dosing of a macrolide

For macrolides, it is necessary to consider whether serum levels or tissue concentrations of these antibiotics are of most importance. Serum concentrations of antibiotics are easily determinable, and rationally there must be a relationship between serum concentrations of an antibiotic and tissue levels, or the concentrations at the site of infection. The relationship is simple for β-lactams and aminoglycosides, which are mostly found in the extracellular compartments, but the situation, is

Acknowledgements

Many of the concepts discussed here have been generated by discussions at meetings of the International Society for Anti-infective Pharmacology (ISAP, http://www.isap.org) and the reader is referred to original publications of this organisation for details. The original experimental work presented here has been made with the support of the Belgian Fonds de Ia Recherche Scientifique Medicale and with a grant-in-aid from Pfizer Inc. F.V.B. is Chercheur Qualifié of the Belgian Fonds National de Ia

References (42)

  • W.A. Craig

    Choosing an antibiotic on the basis of pharmacodynamics

    Ear Nose Throat J.

    (1998)
  • J.J. Schentag et al.

    In nosocomial pneumonia, optimizing antibiotics other than aminoglycosides is a more important determinant of successful clinical outcome, and a better means of avoiding resistance

    Semin. Respir. Infect.

    (1997)
  • J.J. Schentag

    Antimicrobial action and pharmacokinetics/pharmacodynamics: the use of AUIC to improve efficacy and avoid resistance

    J. Chemother.

    (1999)
  • J. Modai

    High-dose intravenous fluoroquinolones in the treatment of severe infections

    J. Chemother.

    (1999)
  • R. Wise

    A review of the clinical pharmacology of moxifloxacin, a new 8-methoxyquinolone, and its potential relation to therapeutic efficacy

    Clin. Drug Invest.

    (1999)
  • G.L. Drusano et al.

    Relevance of the Alexander Project: pharmacodynamic considerations

    J. Antimicrob. Chemother.

    (1996)
  • J.J. Schentag et al.

    AUIC—the universal parameter within the constraint of a reasonable dosing interval

    Ann. Pharmacother.

    (1996)
  • A.P. MacGowan et al.

    Pharmacodynamics of antimicrobial agents and rationale for their dosing

    J. Chemother.

    (1997)
  • J.M. Hyatt et al.

    The importance of pharmacokinetic/pharmacodynamic surrogate markers to outcome: focus on antibacterial agents

    Clin. Pharmacokinet.

    (1995)
  • P. Periti et al.

    Clarithromycin: pharmacokinetic and pharmacodynamic interrelationships and dosage regimen

    J. Chemother.

    (1999)
  • Y. Ouadrhiri et al.

    Mechanism of the intracellular killing and modulation of antibiotic susceptibility of Listeria monocytogenes in THP-1 macrophages activated by gamma interferon

    Antimicrob. Agents Chemother.

    (1999)

    • Cited by (96)

    • Pharmacokinetics, PK/PD analysis and placental transfer of erythromycin administered to pregnant goats

      2023, Small Ruminant Research

    • Antibiotics: Pharmacokinetics, toxicity, resistance and multidrug efflux pumps

      2017, Biochemical Pharmacology
      Citation Excerpt :

      Macrolides have the highest accumulation capacity in eukaryotic cells among the antibiotic classes, and their wide distribution throughout the body makes them an ideal drug for fight against intracellular pathogens [42]. In terms of their PK activity, the members of this group show differences in that while the administration of erythromycin is based on the parameter T > MIC, both T > MIC and AUC/MIC are the crucial parameters for the efficacy of azithromycin and clarithromycin [23,83]. In a recent study, it was shown that current azithromycin doses (500–600 mg in combination therapy) are not sufficient for optimum bacterial killing in pulmonary M. avium infections and only a much higher dose (8 g/day) achieves the target point [84].

    • Pharmacokinetic and pharmacodynamic properties of gamithromycin in Turkey poults with respect to Ornithobacterium rhinotracheale

      2015, Poultry Science

    • Macrolide and Ketolide Antibiotics Inhibit the Cytotoxic Effect of Trastuzumab Emtansine in HER2-Positive Breast Cancer Cells: Implication of a Potential Drug-ADC Interaction in Cancer Chemotherapy

      2023, Molecular Pharmaceutics

    • In vitro pharmacodynamics of nemonoxacin and other antimicrobial agents against Mycoplasma pneumoniae

      2023, Microbiology Spectrum

    • Inherent Fluorescence Demonstrates Immunotropic Properties for Novel Janus Kinase 3 Inhibitors

      2023, ACS Pharmacology and Translational Science
    View all citing articles on Scopus
    View full text
    Copyright © 2001 Published by Elsevier B.V.