Effect of norfloxacin on bacterial flora in human feces
Motohiro, T.; Oda, K.; Aramaki, M.; Kawakami, A.; Tanaka, K.; Koga, T.; Shimada, Y.; Tomita, S.; Sakata, Y.; Fujimoto, T.
Japanese Journal of Antibiotics 40(9): 1584-1616
1987
ISSN/ISBN: 0368-2781 PMID: 3694785 Document Number: 299798
Norfloxacin (NFLX), a synthetic oral antibacterial agent of quinolone carboxylic acid, was given orally for 5 full days at a dose of 200 mg, three times daily after each meal to healthy normal men with ages between 22 and 25 years weighing 53.0 to 84.0 kg (average 67.0 kg). The actual regimen followed was that the drug was administered twice after lunch and supper on the first day of dosing, and once after breakfast on the last day of dosing. On the 5th day before the start of dosing, on the first, 3rd and 5th days (last dosing day) of dosing, and on the 3rd, 5th, 10th and 20th days after the end of dosing, effects of the drug on the fecal flora were examined and its fecal levels were determined. Susceptibilities against NFLX and nalidixic acid (NA) of various fecal isolates from 7 men were determined. Adverse effects and influences on clinical laboratory tests were also examined. The results obtained are summarized below. 1. Following the drug administration, a transient decrease or disappearance of Escherichia coli, Klebsiella sp., Citrobacter sp. and Enterobacter sp. of Enterobacteriaceae was noted. The 3 strains other than E. coli were isolated from increasing number of cases after the end of dosing. No constant trend was observed in the isolation of Proteus sp. Organisms belong to Enterobacteriaceae were isolated only in 4 and 2 cases after 3 and 5 days of the start of dosing, respectively, but then gradually increased to the predose level. Among other Gram-negative bacteria, no constant trend was noted in the isolation frequency of Plesiomonas sp. Pseudomonas sp. was isolated from 6 and 5 cases on the 3rd day after dosing and on the 3rd day after the end of dosing, respectively; the frequency of isolation increased after dosing. Gram-positive bacteria such as Staphylococcus sp. were isolated with a reduced frequency on the 3rd day of dosing. However, the number of isolates increased in all cases both on the 5th day of dosing and on the 3rd day after the end of dosing, and then decreased. No change was noticed in the number of isolates of Enterococcus sp., and no constant trend was observed for Micrococcus sp. and YLO. The average count of the whole aerobic bacteria did not change. Some strains decreased significantly after the start of dosing. 2. Among anaerobes, Bacteroides fragilis and other Bacteroides were isolated on every test day. Although their average counts did not change, in some cases significant decreases were noted in numbers of both groups of bacteria after the start of the dosing. Average counts of Bifidobacterium were significantly lower than normal in 3 and 5 days after the start of dosing and 3 days after the end of dosing, but no change was noted on other days of testing. In some cases, significantly lower counts were noted for Bifidobacterium. No consistent change was seen in the isolation of Lactobacillus. Lecithinase (.sbd.) Clostridium strains except Clostridium difficile were not isolated until 5 days after the end of dosing; they were isolated from 4 and 3 cases at 10 and 20 days after the end of dosing, respectively. Lec. (+) Clostridium strains were isolated more frequently at 3 days after the start of dosing and 5 days after the end of dosing than those before dosing. C. difficile was not isolated from any case until 5 days after the start of dosing nor at 10 and 20 days after the end of dosing. They were isolated from 4 and 5 cases on the 3rd and 5th day after the end of dosing, respectively. From the feces of these cases, C. difficile D-1 toxin was detected. From 1 of the 2 cases from which C. difficile was not isolated, D-1 toxin was detected in the feces at 20 days after the end of dosing. C. difficile and its D-1 toxin were detected in the feces of a number of cases, but the significance of their presence is not known, at this time. A further study with a larger number of cases will be required to determine the relation of the drug effect to the increased frequency of isolation of C. difficile and its toxin. Peptococcaceae strains were isolated from some samples every day of the testing; no change was observed in average bacterial counts. The average count of total anaerobes decreased significantly at 3 days after the start of dosing but did not change after then. 3. In the 7 cases where the drug effects on the fecal flora were examined, average fecal drug levels were 520.7 .mu.g/g, 923.0 .mu.g/g and 101.4 .mu.g/g on the 3rd and the 5th day of dosing and at 3 days after the end of dosing, respectively. The highest drug level was attained on the 5th day of dosing. At 5 days after the end of dosing, the drug level was in a range from 0.6 to 363 .mu.g/ml in 3 cases and was below the detection limit of analysis in 4 cases. At 10 and 20 days after the end of dosing, the drug levels were lower than the detection limit in all cases. 4. Fecal isolates from these cases were tested for their drug susceptibilities to NFLX and NA at an inoculum size of 106 cells/ml. NFLX showed l ower MICs against Gram-positive and Gram-negative bacteria than NA. Changes in the MICs of the drugs against 7 strains of bacteria listed below were examined before, during and after the dosing; Staphylococcus aureus, coagulase-negative Staphylococci, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, C. freundii and Acinetobacter calcoaceticus. Only against coagulase-negative Staphylococci, both drugs showed larger MICs during and after the dosing than MIC's before the dosing. 5. C. difficile was isolated from 5 cases and its fecal D-1 toxin was detected in 6 cases after the end of dosing. However, no adverse digestive effects including diarrhea occurred. On clinical laboratory tests, a slight increase in GPT was noted in 1 case.