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Entry of roxithromycin (RU 965), imipenem, cefotaxime, trimethoprim, and metronidazole into human polymorphonuclear
W L Hand1, N King-Thompson, J W Holman
1Veterans Administration Medical Center (Atlanta), Decatur, Georgia 30033.
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 beta-lactam antibiotics, was taken up poorly by phagocytes (C/E less than or equal to 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 degrees C than at 37 degrees 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.
Insights
Roxithromycin and trimethoprim show high uptake by human phagocytes (PMN). These antibiotics concentrate well within cells, suggesting potential for treating intracellular infections.
Area of Science:
- Pharmacology
- Immunology
- Microbiology
Background:
- Antibiotic entry into phagocytes is crucial for combating intracellular pathogens.
- Understanding antibiotic accumulation in human polymorphonuclear leukocytes (PMN) is key for effective treatment strategies.
Purpose of the Study:
- To evaluate the uptake of five newer antibiotics by human PMN.
- To identify antibiotics with significant intracellular accumulation for potential use against intracellular infections.
Main Methods:
- Utilized velocity gradient centrifugation to measure antibiotic uptake by PMN.
- Expressed uptake as the cellular to extracellular concentration ratio (C/E).
- Investigated roxithromycin uptake kinetics and the effect of particle ingestion.
Main Results:
- Roxithromycin demonstrated the highest PMN concentration (C/E = 34), indicating active, carrier-mediated transport.
- Trimethoprim also showed significant PMN accumulation (C/E = 9-13), with higher uptake at 25°C than 37°C.
- Cefotaxime and metronidazole had poor to moderate PMN uptake, while imipenem showed rapid binding but declining levels.
Conclusions:
- Roxithromycin and trimethoprim are markedly concentrated within human PMN.
- These findings highlight the potential therapeutic value of roxithromycin and trimethoprim for infections caused by intracellular organisms.