04/18/23 ISAP - 2009 1

Is the cellular accumulation of antibiotics a predictive factor

for intracellular efficacy ?

Sandrine Lemaire

Université catholique de Louvain & Louvain Drug Research Institute

Brussels, Belgium

04/18/23 ISAP - 2009 2

Persistence and recurrence:

the case of Staphylococcus aureus …

Intracellular Staphylococcus aureus. A mechanism for the indolence of osteomyelitisEllington et al, J Bone Joint Surg (2003), 85:918-921.

Intracellular persistence of Staphylococcus aureus Small Colony Variants within keratinocytes: a cause for antibiotic treatment failure in a patient with Darier’s disease. von Eiff et al, Clin Infect Dis (2001), 32:1643-1647.

Phagocytosis of Staphylococcus aureus by macrophages exerts cytoprotective effects manifested by the up-regulation of antiapoptotic factors. Koziel et al, PLoS One (2009), 4:e5210.

Staphylococcus aureus an intracellular pathogen: the role of Small Colony Variants. Sendi and Proctor, Trends Microbiol (2009), 17:54-58

…

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A simple scheme ?

Cellular accumulation

Antibiotic

Antibacterial effect

Phagolysosomial infection

phagolysosomes

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1st exemple: Torezolid (TR-700), a novel oxazolidinone

3-{3-Fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-pyridin-3-yl]-phenyl}-5-hydroxymethyl-oxazolidin-2-one

O

N

O

HON

NN

NN

F

O

HN

O

N

O

N O

F

N-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide

TR-700 / DA-7157

linezolid

Comparative cellular accumulation

Torezolid accumulates quickly within cells, reaching an apparent cell. to

extracell. concentration ratio of 12.5 – 15.

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Torezolid vs. linezolid

Lemaire et al, JAC, 2009

Torezolid is more active than linezolid against

the intracellular forms of S. aureus (ATCC 25923)

On a weight concentration basis, torezolid is 4-fold more potent than linezolid against intracellular forms of S. aureus.

* Cs, Static concentration

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Torezolid vs. linezolid

Lemaire et al, JAC, 2009

When data are plotted against equipotent concentration (MIC multiples), torezolid and linezolid show undistinguishable concentration-dependent activities against intracellular forms of S. aureus

This indicates that the main driver of torezolid intracell. activity is not the marked cell. accum, but its higher intrinsic activity

Torezolid is more active than linezolid …Is it still true when comparing equipotent concentrations ?

Torezolid vs. Linezolid against others intracell. bacteria

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Cytosolic model Phagosomal model

MICs: L.M., TR-700, 0.125 mg/L vs LZD, 1 mg/L; L.P., TR-700, 0.25 mg/L vs LZD, 8 mg/L

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2nd exemple: CEM-101, a novel fluoroketolide

Comparative cellular accumulation

CEM-101 accumulates to a larger extent than clarithromycin (CLR) and telithromycin (TEL)

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CEM-101 vs. comparators

CEM-101 is more active than CLR and TEL against intracellular forms of S. aureus (strain ATCC 25923)

On a weight concentration basis, CEM-101 expresses consistently greater potency (decreases values of EC50 and Cs) and slightly higher efficacy (Emax) than comparators.

Lemaire et al, AAC (2009), 53:3734-3743

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CEM-101 vs. comparators

If we consider equipotent concentrations of antibiotics …

When data are plotted against equipotent concentration (MIC multiples), the differences in EC50 and static concentrations between drugs were minimized.

This indicates that the main driver of CEM-101 intracell. activity is not the marked cell. accum, but its higher intrinsic activity

* MICs at pH 7.4: CLR, 0.5 mg/L; TEL, 0.25 mg/L; CEM-101, 0.06 mg/L

*

Lemaire et al, AAC (2009), 53:3734-3743

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Is it still a simple scheme ???

Cellular accumulation

Antibiotic

These studies demonstrate the critical role of intrinsic drug activity (MIC) in eliciting the antibacterial intracellular effects of TR-700 and CEM-101 whereas their

increased cellular accumulation per se play only a minimal role.

Antibacterial effect

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Other factors ???

Cellular penetration

Antibiotic

Metabolism

Binding Cooperation with host defences

Physical or biochemicalConditions prevailing

in the infected site

Influx vs. efflux Bacterial stress response

Thank you for your attention

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