Cells of Escherichia coli Neumann and E. coli KL16 were suspended in phosphate-buffered saline pH 7.4 and allowed to reach stationary growth conditions. Ciprofloxacin was added at different concentrations, and time-kill curves were constructed. It could be demonstrated that the number of viable cells was reduced quickly by several logs for E. coli Neumann, whereas a weak and slow killing effect was observed with E. coli KL16. When ciprofloxacin or norfloxacin was added to logarithmically growing cultures of E. coli Neumann or E. coli KL16, no principal differences in the killing rate for the two strains could be observed. Ciprofloxacin, however, was more bactericidal than norfloxacin. It was also demonstrated that the bactericidal action of ciprofloxacin on cells in the stationary growth phase was better at pH 7.4 than at pH 8.6. This dependence is different from that observed in MIC studies, in which the MIC were lower at pH 8.0 than at pH 7.2. It was also found that the bactericidal action of ciprofloxacin or norfloxacin on cells of E, coli Neumann in the stationary phase of growth could not be reduced by the addition of chloramphenicol, whereas under conditions of logarithmic growth the rapid killing effect of ciprofloxacin was reduced in the presence of chloramphenicol.Ciprofloxacin, a new quinolone derivative with a broad antibacterial spectrum (1,3,5,7,9), has become the subject of many in vitro studies. Ciprofloxacin has been characterized by its extraordinary killing effect on bacteria which are in a stationary phase of growth (10). Furthermore, it has been shown that the killing effect of ciprofloxacin or norfloxacip on actively growing cells is antagonized in the presence of chloramphenicol or rifampin (4,7,8). It was also reported that ciprofloxacin or ofloxacin must have an additional bactericidal action, which makes these two quinolones more independent from the antagonistic influence of chloramphenicol or rifampin (8). This paper reports results that concern the killing activity of ciprofloxacin on cells of different strains of Escherichia coli in the stationary phase of growth. The effect of pH and the influence of chloramphenicol under such conditions are also described and compared with those under normal growth conditions in broth. MATERIALS AND METfIODSOrganisms. The test strains used were isolates from the strain collection of the Institute of Chemotherapy, Bayer AG, Wuppertal, Federal Republic of Germany. E. coli KL16 (6) was originally obtained from J. T. Smith, School of Pharmacy, University of London, London, England.Antibacterial agents. The test substances were ciprofloxacin, norfloxacin (synthesized at Bayer AG), and chloramphenicol (Sigma Chemical Co.).MICs. MICs were measured by broth dilution techniques in microtiter trays (Greiner). Serial dilutions of 0.1 ml of the agents used were prepared in Isosensitest broth (Oxoid). To these were added 0.1 ml of a 1:1,000 dilution of an overnight culture of organisms, ending in a final inoculum of 1 x 105 to 2 x 105 CFU/ml. The microtiter pla...
The antibacterial activity of ciprofloxacin (Bay o 9867) was compared with those of norfloxacin, nalidixic acid, trimethoprim-sulfamethoxazole, cefaclor, sisomicin and cefotaxime in in vitro and mouse protection studies. Approximately 300 clinical isolates of clinically important gram-positive and gram-negative species were used. The median MICs of ciprofloxacin against gram-positive and gram-negative bacteria ranged from less than or equal to 0.015-1 mg/l. Ciprofloxacin was 2-8 fold more active than norfloxacin and 100-fold more active than nalidixic acid. It also had a wider spectrum of activity against gram-positive organisms including even enterococci. No cross-resistance was observed between ciprofloxacin and beta-lactam antibiotics or aminoglycosides. Only acidic pH conditions decreased its activity. Ciprofloxacin showed rapid bactericidal action against organisms in both the logarithmic and stationary growth phases. In mouse protection studies (intraperitoneal infection) ciprofloxacin was significantly more effective than norfloxacin, ampicillin, trimethoprim-sulfamethoxazole, and also showed excellent activity against Pseudomonas infections.
SUMMARYCiprofloxacin (ClP)isa quinolonccarboxylicacid derivative with a broad spectrum of antibacterial activity. CIP (01-30 /jg/ml) enhanced DNA synthesis of mouse spleen eells and human peripheral blood lymphocytes (PBL) that had been activated with T eell mitogens or with alloaiitigens. In addition, CIP increased thc amount of IL-2 found in thc supernatants of phylohaemagglutinin (PHA)-stimulated human PBL, The presence of CIP in the medium ({)-3-IO /(g/ml) increased the levels of IL-1 found in Ihe eulture supernatants of adherence-enriched mouse macrophages. human monocyte/maerophages and a human monocytie cell line stimulated with lipopolysaecharide. In contrast there was no effeet of CIP on Ihe release of IL-I by freshly isolated human monocytes or by cells ofthe keratinocyte line, A431. CIP alone had no influence on the basal release of 1 L-2 by NOB-I cells, a Teell line that responds to IL-1 with an increase in lL-2 synthesis, but. in combination with recombinant IL-I, CIP significantly enhanced the release of IL-2 by these cells. The results ofthis study suggest that CIP modulates the immune response at two levels -the production of IL-2 by activated Tcells and the production of IL-1 by aeliva ted monocyte/maerophages. However, CIP did not affect the primary antibody response in vitro or in vivo against sheep erythroeytes and ovalbumin respectively. Thus the enhancing action of ciprofloxacin on the immune system appears to be restricted to T cell funciion and macrophagc/T cell interactions.
A 200 mg oral dose of ciprofloxacin, norfloxacin or ofloxacin was administered to six healthy male volunteers in a three way cross-over study in order to examine the kinetics in humans in relation to the bactericidal activity in serum and urine. Serum concentrations for ciprofloxacin were similar to norfloxacin and lower than ofloxacin. Despite this fact, ciprofloxacin showed the highest serum bactericidal titers compared to norfloxacin and ofloxacin when serum-resistant Escherichia coli C14 was used as a test organism. These results correlate with observations from timekill curve studies in human whole blood, where ciprofloxacin showed superior bactericidal activity compared to norfloxacin or ofloxacin. The amounts of unchanged drug excreted in urine (48 h period) were found to be 35%, 24% and 77% for ciprofloxacin, norfloxacin and ofloxacin respectively, indicating different excretion kinetics. The volumes of urine excreted in the different collection periods were comparable for the three drugs tested. Mean urine concentrations for ciprofloxacin were higher during the 0 to 4 h collection periods, whereas ofloxacin was excreted into the urine over a longer time period. Measurements of urine bactericidal activity showed that ciprofloxacin had the highest titers during the early collection periods, whereas the prolonged excretion of ofloxacin did not result in higher urine bactericidal titers, compared to ciprofloxacin.
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