Mouse macrophages and J774 macrophage-like cells express probenecid-inhibitable organic anion transporters that remove anionic dyes from the cells' cytoplasmic matrix and secrete these dyes into the extracellular medium. The present studies show that these transporters also secrete antibiotics from J774 macrophages. Penicillin G permeates J774 cells poorly, but after it was introduced into the cell cytoplasm, it was secreted in a probenecid-inhibitable fashion. The quinolone norfloxacin enters macrophages readily. Probenecid retarded the secretion of intracellular norfloxacin by J774 cells and enhanced norfloxacin accumulation three- to fourfold. Thus the intracellular accumulation of norfloxacin is regulated in part by organic anion transporters that secrete norfloxacin (and penicillin G) from J774 cells. This transport process may have clinical significance, as fluoroquinolones inhibit growth of intracellular pathogens such as mycobacteria and Brucella organisms in vitro but fail to arrest infections with these organisms in vivo.

GFZ intensified the bacteriostatic effect of 4 Ag/ml NFX and rendered 8 ltg/ml bactericidal for L . monocytogenes . GFZ had a similar potentiating effect when used in combination with 2 ug/ml ciprofloxacin (CFX) . CFX plus GFZ was bactericidal for intracellular L . monocytogenes . Treatment of J774 cells with NFX plus GFZ markedly reduced the cytotoxic effect of the bacteria on these cells . Over 55% of cells treated with 8 Ag/ml NFX alone were dead 16 h after infection, whereas only 5% of cells treated with 8 p,g/ml NFX plus GFZ were dead at 16 h. Similarly, GFZ potentiated the ability of 2 NAg/ml to protect J774 cells against the cytocidal effect of Listeria. NFX in combination with GFZ limited cell-to-cell spread of L . monocytogenes . In antibiotic-free medium, >99% of J774 cells contained intracellular L . monocytogenes at 14 h after infection . NFX alone in the medium did not change this outcome . However, 4 p,g/ml NFX plus GFZ decreased bacterial spread by approximately 40% at 24 h postinfection, and 8 lAg/ml NFX plus GFZ prevented all spread beyond the initially infected cell population . These results suggest that GFZ could be used clinically to enhance the efficacy of fluoroquinolone and of other anionic antibiotics against bacteria that grow and/or reside within macrophages and/or other cells .

LY163892 is a new orally absorbed carbacephem. It inhibited Streptococcus pyogenes and Str. pneumoniae at less than or equal to 1 mg/l, but was less active against group B streptococci and groups C, F, G and bovis streptococci with MICs of 1 to 2 mg/l for most but as high as 8 mg/l for some isolates. MIC90 of methicillin-susceptible Staphylococcus aureus was 8 mg/l, but greater than 128 mg/l for methicillin-resistant staphylococci. LY163892 had activity similar to cefaclor and cephalexin with MIC90 values of 16 mg/l for Escherichia coli, 8 mg/l for Klebsiella pneumoniae, Proteus mirabilis, Yersinia enterocolitica, but was more active against Haemophilus influenzae, and Branhamella catarrhalis. It had no activity against Enterobacter, Providencia, Serratia, and Pseudomonas and Bacteroides spp. LY163892 was more rapidly lytic than cephalexin. It was hydrolyzed by a number of plasmid and chromosomal beta-lactamases. For TEM-1, the Km = 354.7 microM, Vmax = 2.5 microMoles/min/mg of protein, P99 Km = 24.3 microM, Vmax = 28.9 microM/min/micrograms of protein, Staph. aureus PC Km = 47.4 microM, Vmax = 2.7 microMoles/min/mg of protein. Overall it had beta-lactamase stability similar to cefaclor, less than cephalexin, and markedly less than cefuroxime.

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