Entry of roxithromycin (RU 965), imipenem, cefotaxime, trimethoprim, and metronidazole into human polymorphonuclear leukocytes

Abstract

Entry of antibiotics into phagocytes is necessary for activity against intracellular organisms. Therefore, we examined the uptake of five of the newer antibiotics-roxithromycin (RU 965), imipenem, cefotaxime, trimethoprim, and metronidazole-by human polymorphonuclear leukocytes (PMN). Antibiotic uptake by PMN was determined by a velocity gradient centrifugation technique and expressed as the ratio of the cellular concentration of antibiotic to the extracellular concentration (C/E). Cefotaxime, like other I-lactam antibiotics, was taken up poorly by phagocytes (C/E ' 0.3). The metronidazole concentration within PMN was similar to the extracellular level. Imipenem bound rapidly to phagocytes (C/E = 3), but cell-associated drug progressively declined during the incubation period. Trimethoprim was well concentrated by PMN (C/E = 9 to 13), and uptake was unexpectedly greater at 25°C than at 37°C. The most striking finding was that roxithromycin was more avidly concentrated by PMN (C/E = 34) than any other antibiotic we studied. Entry of roxithromycin into phagocytes was an active process and displayed saturation kinetics characteristic of a carrier-mediated membrane transport system. Ingestion of microbial particles by PMN slightly decreased the ability of these cells to accumulate roxithromycin (C/E = 24 to 31). These studies identified two antibiotics, trimethoprim and especially roxithromycin, which are markedly concentrated within human PMN and may prove useful in treatment of infections caused by susceptible intracellular organisms.

Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or "Immuno-Fairy Tales"?

“…Binding to intracellular targets in PMNs has also been proposed for erythromycin A (311). Some authors have proposed the nucleoside transport system for josamycin uptake (216) and another (unidentified) carrier for roxithromycin (138). Results from our group have confirmed the existence on the PMN membrane of an active saturable transport system common to all macrolides (and their recently synthesized derivatives, ketolides) which displays different affinities depending on the macrolide structure (398,399).…”

Cellular Uptake of Two Fluoroketolides, HMR 3562 and HMR 3787, by Human Polymorphonuclear Neutrophils In Vitro

“…The literature on the cellular uptake of these drugs supports the existence of an active transport system, at least in phagocytic cells (6,9,23,24).…”

A New Era of Pulmonary Delivery of Nano-antimicrobial Therapeutics to Treat Chronic Pulmonary Infections

“…Eradication of intracellular organisms presents severe challenges as therapeutic concentrations of antimicrobials in intracellular compartments are difficult to achieve due to their limited penetration capacity [210,211]. Thus, many antibiotics, such as -lactam and aminoglycoside antibiotics show low concentrations in intracellular compartments due to poor penetration and acidic and enzymatic degradation.…”

“…However, water-soluble quinolone and macrolide antibiotics, such as clindamycin, levofloxacin, etc. attain higher intracellular concentrations as opposed to extracellular concentrations [210][211][212]. Mycobacterium tuberculosis binds to and internalizes in the alveolar macrophages as a survival mechanism, and hence is very difficult to eradicate completely.…”