Tissue Penetration of Antimicrobials in Intensive Care Unit Patients: A Systematic Review—Part II

Abstract

In patients that are admitted to intensive care units (ICUs), the clinical outcome of severe infections depends on several factors, as well as the early administration of chemotherapies and comorbidities. Antimicrobials may be used in off-label regimens to maximize the probability of therapeutic concentrations within infected tissues and to prevent the selection of resistant clones. Interestingly, the literature clearly shows that the rate of tissue penetration is variable among antibacterial drugs, and the correlation between plasma and tissue concentrations may be inconstant. The present review harvests data about tissue penetration of antibacterial drugs in ICU patients, limiting the search to those drugs that mainly act as protein synthesis inhibitors and disrupting DNA structure and function. As expected, fluoroquinolones, macrolides, linezolid, and tigecycline have an excellent diffusion into epithelial lining fluid. That high penetration is fundamental for the therapy of ventilator and healthcare-associated pneumonia. Some drugs also display a high penetration rate within cerebrospinal fluid, while other agents diffuse into the skin and soft tissues. Further studies are needed to improve our knowledge about drug tissue penetration, especially in the presence of factors that may affect drug pharmacokinetics.

Maternal antibiotic administration during gestation can affect the memory and brain structure in mouse offspring

“…Furthermore, a positive trend close to the statistical significance of the permeability of BBB was observed in those offspring ( Supplementary Figure 3B ). These findings corresponded to the previously published reports that both amoxicillin and azithromycin penetrate the blood brain barrier in healthy individuals even without CNS inflammation ( Mingrino et al, 1981 ; Viaggi et al, 2022 ), and antibiotics may contribute to the BBB breakdown in offspring ( O’Connor et al, 2021 ). Besides the role of BBB in central nervous protection, it also engaged in behavioral disorders ( Dion-Albert et al, 2022 ).…”

Anti‑CXCR4 chemokine receptor, motixafortide, as an adjunct treatment with anti‑TB drugs decreases the bacterial burden by improving drug distribution

“…The inefficiency and long-term treatment strategy of anti-TB drugs are considered to be sources of pharmacokinetic factors (40). Aside from the complex array of diseased sites, the vasculature within granuloma impedes drug delivery (41). According to a previous study, CXCR4 has been linked to tumour angiogenesis via transcriptional regulation of VEGF signalling (42).…”

When and How to Use MIC in Clinical Practice?

“…TDM is mainly performed on plasma samples and may not reflect antibiotic exposure at the site of infection, particularly in cases of endocarditis, mediastinitis, central nervous system infections, pneumopathy, or infections on prosthetic material [ 6 ]. It is thus important to consider the diffusion of antibiotics in the tissues concerned and to adapt the plasma target accordingly [ 70 , 71 ]. For example, when considering lung diffusion, the criterion of interest is the ratio of epithelial lining fluid (ELF) concentration to plasma concentration (ELF/plasma ratio).…”

“…For example, when considering lung diffusion, the criterion of interest is the ratio of epithelial lining fluid (ELF) concentration to plasma concentration (ELF/plasma ratio). Antibiotics are then classified according to their diffusion with (i) ELF/plasma ratio < 1: vancomycin, meropenem, and piperacillin; (ii) ELF/plasma ratio ~1: cefepime and linezolid; and (iii) ELF/plasma ratio > 1: fluoroquinolones and azithromycin [ 70 , 71 ]. Antibiotics with the highest diffusion will be thus be useful for organisms with a high MIC.…”