Antibiotic exposure at the site of infection: principles and assessment of tissue penetration

ABSTRACT

Introduction: Since the majority of bacterial infections occur at sites outside the bloodstream, antibiotic tissue concentrations are of significant relevance to optimize treatment. The aim of this review is to aid the clinician in choosing optimal regimens for the treatment of extravascular infections.

Areas covered: We discuss the principles of antibiotic tissue penetration and assess different approaches to obtain data on this subject. Finally, we present tissue penetration data for several relevant groups of antibiotic agents in a number of extravascular sites. Data were obtained from an extensive literature search in PubMed until February 2019.

Expert opinion: There is still a long way to go before reliable information about tissue penetration of antibiotics is sufficiently available to serve as a basis for the design of optimal strategies for drug and dose selection. At this moment, there is a lack of robust data on tissue penetration, where both the sampling and measurement techniques as well as the relationship between tissue concentrations and clinical outcome of antibiotic treatment have to be better defined.

KEYWORDS:

• Antibiotics
• infection
• microdialysis
• pharmacokinetic
• tissue distribution
• tissue penetration

Article highlights

• Antibiotic tissue penetration and distribution depend on various factors; drug characteristics (molecular weight, protein binding, lipid solubility and degree of ionization), target tissue characteristics (membrane function and vascularization of the tissue) and the presence or absence of inflammation

• In general, small (<1000 Da) lipophilic agents with low protein binding show a high degree of tissue penetration and are capable of entering and readily accumulating in tissue cells. Conversely, hydrophilic agents tend to remain in the interstitial fluid and do not enter tissue cells

• Agents with a high molecular weight and highly protein bound agents show a lower degree of tissue penetration

• For agents with a wide therapeutic range and where tissue to serum concentration ratios are small, increasing systemic doses may result in adequate tissue concentrations without significantly increasing the risk of toxicity

• More robust investigation on the relationship between tissue concentrations and clinical outcome is required, with target concentrations from in vitro infection models yet to be validated in vivo

Declaration of interest

RM van Hest has provided consultancies for Nordic Pharma. J Lipman is a member of the Bayer ESICM Advisory Board and the MSD Antibacterials Advisory Board, received an honorarium for lectures for Pfizer South Africa and MSD South Africa and is a member of the Pfizer International 2018 Anti-Infectives committee. JA Roberts wishes to acknowledge funding from the Australian National Health and Medical Research Council for Centre of Research Excellence (APP1099452) and a Practitioner Fellowship (APP1117065). JA Roberts has provided lectures/consultancies or had grant funding provided to his institution from MSD, Astellas, Biomerieux, Accelerate Diagnostics, Cardeas Pharma. MO Cotta is supported by a Postdoctoral Development Fellowship from The University of Queensland.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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