[Effect of biapenem (L-627) on fecal flora in gnotobiotic mice and children].

Biapenem (L-627), a novel injectable carbapenem antibiotic, was studied with regard to its effect on mice inoculated with four types of bacteria and on the intestinal flora of pediatric patients. L-627 was given i.m., 40 mg/kg once daily for 5 consecutive days, to mice inoculated enterically with four types of bacteria (Escherichia coli, Enterococcus faecalis, Bacteroides fragilis, and Bifidobacterium breve). Except for a mild decrease in E. coli, there were no major fluctuations in viable bacterial counts in the feces during the treatment. Five children with bacterial infections (3 boys and 2 girls; ages: 1 month to 7 years and 7 months; body weights 4.62-21.8 kg) were given L-627 at 6.0 to 11.7 mg/kg 3 times daily for 7 to 11 days. Among aerobes, although Enterobacteriaceae such as E. coli tended to decrease remarkably in all patients, there was no major change in Enterococcus. Consequently, total aerobe counts did not change significantly in any patient. Among anaerobes, Bifidobacterium, Bacteroides, and Eubacterium, which are the predominant organisms in infants, decreased remarkably in some patients. One of the patients showed a marked decrease in total anaerobe count associated with a change in fecal characteristics (diarrhea). Glucose nonfermenting Gram-negative bacilli or fungi did not become predominant organisms in any patient. Recovery from these changes in the intestinal flora was noted promptly after terminating L-627 treatment. L-627 was detected in the feces of 4 patients during treatment. The fecal concentration ranged from 0.24 to 2.22 micrograms/g. Clostridium difficile was not detected in any patient. Although C. difficile D-1 antigen was observed in 2 patients, it bore no relationship to fecal properties. The results indicated that L-627 had relatively few effects on the intestinal flora compared to other new beta-lactam antibiotics.

[Influence of S-1108 on intestinal bacterial flora].

The effect of S-1108, a new oral cephem antibiotic, on intestinal bacterial flora was studied in tetra-contaminated mice and pediatric patients. S-1108 in a fine granular form was administered at a dose of 15 mg/kg once a day for 5 consecutive days to mice infected with Escherichia coli, Enterococcus faecalis, Bacteroides fragilis and Bifidobacterium breve. The viable fecal bacterial cell count of each of these 4 species of bacteria was slightly reduced in 5 days after the start of the drug administration. Five boys (weighing 12.0 to 42.0 kg) with bacterial infections were entered into this pediatric study. Their ages ranged from 2 years 4 months to 9 years 3 months. S-1108 (fine granules) was administered at a dose of 2.3 to 6.0 mg/kg, 3 times a day for 5 to 11 days. Cell counts of primary aerobes, anaerobes and total anaerobic cells decreased markedly in three patients, but in the remaining two patients the total number of aerobic and anaerobic cells did not change appreciably. Glucose-nonfermentating Gram-negative rods did not become predominant during the period of S-1108 administration. Candida became predominant in the three patients in whom the other bacteria had markedly decreased. Counts of predominant aerobic and anaerobic bacteria decreased markedly during the regimen in 3 out of 5 cases. S-1006 was detected in stools of the 3 cases at concentrations ranging from 235 to 516 micrograms/g during the administration of S-1108. Intestinal bacteria that produce beta-lactamase were not present in the feces of any of the patients. Based on these results, S-1108 (fine granules) appears to have relatively little effect on intestinal bacterial flora similarly to other new oral cephems. Because of individual differences, however, the drug may be excreted in the feces at high concentrations, and this would result in changes in intestinal bacterial flora. Therefore, attention must be given to fecal drug concentrations.

[The influence of cefprozil on intestinal bacterial flora].

Cefprozil (CFPZ, BMY-28100), a new oral cephalosporin antibiotic, was studied for its effect on the intestinal bacterial flora in pediatric patients. The subjects were children admitted for infections (2 males and 2 females, 9 months to 6 years 3 months old, weighed 4.3 to 19.0 kg). CFPZ granule was orally administered at a dose between 10.0 to 11.6 mg/kg, 3 doses daily, over 4 to 14 days. The feces from these children were collected before, during and after administration, and bacteria were identified and counted. CFPZ concentration, beta-lactamase activity were also assayed. Bacterial flora in feces during CFPZ administration showed some variance, but no significant change was observed in main aerobes and anaerobes. And in no case, glucose nonfermentative Gram-negative bacilli or fungi were found dominant. beta-Lactamase activity was positive in the feces in all cases. CFPZ concentrations were not detectable in feces before, during and after administration. The above results suggest that CFPZ is a drug with little influence on the intestinal bacterial flora in children.

[Effect of meropenem on fecal flora in children].

Meropenem (MEPM, SM-7338), a novel parenteral carbapenem antibiotic, was examined for its effect on intestinal flora in children. Seven children with infectious diseases (3 male and 4 female children of age's ranging from 4 months to 8 years and 9 months weighing from 7.3 to 23.0 kg) were treated with MEPM at doses ranging 10.3 to 40.5 mg/kg 3 or 4 times a day for 6 to 12 days. Before, during and after the treatment, identities and numbers of various bacteria contained in 1 g of feces were determined and fecal beta-lactamase activity and Clostridium difficile D-1 antigen were also assayed. Changes in fecal flora during MEPM treatment was somewhat different depending on cases. Regarding Enterobacteriaceae among aerobes, all of 7 cases exhibited moderate or pronounced reductions in Escherichia coli. Some of the cases exhibited the tendency to increase in Klebsiella oxytoca. Enterobacter cloacae and Citrobacter freundii. E. coli which was reduced during the treatment increased rapidly after the treatment in 5 out of 7 cases, and the initial bacterial counts were restored. Diverse strains were observed within the genus Enterococcus, while the overall bacterial counts of this genus exhibited the tendency to increase during the treatment. As a result, no significant change in total aerobe count was observed in any case except 1 case where Enterococcus count was somewhat reduced. Among anaerobes, major bacteria such as Bacteroides, Bifidobacterium, Eubacterium and Peptococcaceae exhibited tendencies to decrease in some cases during the antibiotic treatment. Two infants and 1 child exhibited significant decreases in total anaerobe counts. In most of the cases, such changes in major anaerobes were transient and bacterial counts recovered to their initial values rapidly after completion of the treatment. In no cases, glucose non-fermentative Gram-negative bacilli or fungus became predominant. Although C. difficile D-1 antigen was observed in 4 cases, its changes had no relationship with characteristics of feces. C. difficile was not detected in any of the cases. MEPM was detected in feces in 4 cases being treatment, in concentrations ranging from 0.35 to 66.0 micrograms/g. Fecal MEPM levels were very low except in 1 case in which beta-lactamase was negative. From these results, effects of MEPM on intestinal flora in children were relatively minor compared to other new beta-lactam drugs. However, a care should be taken to minimize diarrhea and bacterial turnover when a prolonged use of the antibiotic, was practiced because of potential significant effects on intestinal flora.

Effects of inline filtration on delivery of gentamicin at various flow rates.

The effects of inline filtration on delivery of gentamicin (GM) in the pediatric field were studied. The filter sets (Pall 0.20 micron. JMS 0.20 micron, and IVEX 2.022 micron) were studied using a simulated system. 10 mg of GM was injected into the system containing 5% dextrose in water (flow rate: 50 ml/hr, 10 ml/hr and 2 ml/hr) with horizontal and vertical settings of the inline filters. In case of 50 ml/hr, delivery of GM of Pall showed nearly the same delivery pattern as compared with no filter setting. However, JMS and IVEX 2 showed little differences. In case of 10 ml/hr and 2 ml/hr those differences became more significant. Delivery of GM was influenced by the priming volume of the filters, increasingly so at slow flow rates. Filter settings also influenced the delivery of GM. Furthermore, with regards to the results of the Vitamin K2 delivery and the technetium radiotracer method, JMS and IVEX 2 filters were observed to have some stagnation of drugs in the filter. Not only priming volumes of the filters affect delivery of drugs, filter designs also have an influence. The use of the inline filters is important in the pediatric field, but their charactaristics for drug delivery pattern should be considered.

[The influence of cefdinir on the intestinal bacterial flora].

The influence of cefdinir (CFDN), a new oral cephalosporin, on the intestinal bacterial flora was studied in tetra-contaminated mice and in pediatric patients. CFDN in fine granules was administered at a dose of 10 mg/kg once a day for 5 consecutive days to mice contaminated with 4 different species of organism: Escherichia coli, Enterococcus faecalis, Bacteroides fragilis and Bifidobacterium breve. No remarkable changes were observed in the fecal viable cell counts except that decreases in E. coli counts were observed on the day 3 to 5 after starting administration. The subjects in pediatric study were 7 children with infections, 3 boys and 4 girls, with their ages from 6 months to 12 years 7 months. Their body weights ranged from 5.5 to 29.2 kg. CFDN fine granules was administered at each dose of 3.0 mg/kg to 3.7 mg/kg, 3 times a day for 4 to 14 days. During the administration of CFDN, some variations were observed in the pattern of changes in the fecal bacterial flora between subjects. Although Enterobacteriaceae and total counts of anaerobes were markedly decreased in 2 cases, total counts of aerobes were unchanged in the 2 cases, whereas main aerobes and anaerobes except enterococci hardly varied in the other cases. There was no case in which glucose non-fermenting Gram-negative rods and fungi became predominant species continually. Although Clostridium difficile and C. difficile D-1 antigens were detected in 1 and 4 cases, respectively, no relationship was found between the number of C. difficile and the characteristics of the feces. With regard to the drug sensitivities of bacteria isolated from feces before and after administration of CFDN, higher levels of resistance were found in some bacteria such as Enterococcus and Bacteroides during or after administration than before administration. CFDN was detected in fecal samples from 2 cases during administration with concentrations ranging between 0.99-254 micrograms/g. High value of CFDN was found in a case with low beta-lactamase activity in feces, in which marked decrease of Enterobacteriaceae and total counts of anaerobes was observed. The above results suggest that CFDN is considered to be a drug with relatively small influence on the intestinal bacterial flora. But as high concentrations of drugs were detected in feces under some circumstances, our attention will be required. Particular care is also required for the occurrence of diarrhea and microbial replacement during continuous, long-term administration of the drug.

[Pharmacokinetics and clinical efficacy of flomoxef in neonates].

Clinical pharmacology and efficacy of flomoxef (FMOX) in neonates were investigated. And the following results were obtained. 1. Mean serum concentrations of FMOX at 30 minutes after administration were 24.3 micrograms/ml, 47.6 micrograms/ml, and 85.8 micrograms/ml at doses of 10 mg/kg, 20 mg/kg, and 40 mg/kg administered, respectively. 2. Mean serum half-lives of FMOX were 3.4 hours in 0-3 day-old neonates, and 2.6 hours in 4 day-old or older subjects. 3. A dose response was evident among different dose groups given 10 mg/kg, 20 mg/kg, and 40 mg/kg. 4. Urinary recovery rates of FMOX in the first 6 hours after administration ranged between 12.8 and 51.1%. 5. FMOX was effective in 7 out of 8 cases in which causative pathogens were identified. 6. Diarrhea was observed in 1 case as a side effect of the drug, but the symptom was relieved soon after the completion of the treatment. There was no case in which any abnormal laboratory results were observed. 7. FMOX has a broad spectrum of activities against Gram-positive and Gram-negative aerobes and anaerobes. It is stable against most of beta-lactamases. It was demonstrated to be highly effective in our study, and yet without any serious side effects. FMOX is therefore considered to be one of the useful agents of the first choice for the treatment of bacterial infections such as sepsis and urinary tract infections in neonates and infants.

[The influence of cefpirome on intestinal bacterial flora].

Cefpirome (CPR, HR810), a new parenteral cephalosporin antibiotic, was studied for its effect on the intestinal bacterial flora in pediatric patients. The subjects were children admitted for infections (6 males and 3 females, 1 month to 5 years 1 month old, weighted 3.94 to 21.0 kg). CPR was intravenously administered at a dose between 19.0 to 40.0 mg/kg, 3 to 4 doses daily over 6 to 12 days. The feces from these children were collected before, during, and after administration, and bacteria were identified and counted. CPR concentration, beta-lactamase activity, and Clostridium difficile D-1 antigen were also assayed. Bacterial flora changes in feces during CPR administration showed some variance, but generally 5 cases out of the 9 showed a significant decrease in Enterobacteriaceae and Enterococcus faecalis among aerobic bacteria. The other 4 cases showed some transient decrease, but no significant change was observed. No significant changes were recognized for Enterococcus avium and Enterococcus faecium, and the total aerobic bacterial count decreased in a transient manner in only one patient. Regarding anaerobic bacteria, Bifidobacterium and Eubactrium revealed a significant decrease, a transient decrease or no change from case to case. Bacteroides showed little change in count. Consequently, the total anaerobic bacteria count did not reveal a large change aside from 1 case in which Bacteroides was not detected before administration and a significant decrease of other bacteria was noted. In no case, glucose nonfermentative Gram-negative bacilli or fungi were found dominant. Although C. difficile and C. difficile D-1 antigen were detected in 3 and 4 cases, respectively, there was no exact relationship between the number of C. difficile and the characteristics of the feces. CPR was detected in fecal samples from 6 cases during administration with concentrations ranging between 1.20 to 22.4 micrograms/g. High values of CPR tended to be found in specimens with low beta-lactamase activity in the feces. When drug sensitivities of the bacteria isolated from feces before and after administration were compared, higher levels of resistance were found in some bacteria such as Enterococci and Bacteroides during or after administration than before administration. The above results suggest that CPR is a drug with a relatively small influence on the intestinal bacterial flora in children, but a particular attention is required for diarrhea and microbial replacement during a continuous, long-term administration of the drug.

[Pharmacokinetics and clinical safety of aztreonam in neonates].

Clinical pharmacology and safety of aztreonam (AZT) in the neonatal period were investigated. The results obtained are summarized as follows. 1. Serum concentrations of AZT at 30 minutes after administration of 10 mg/kg were 22.1-32.2 micrograms/ml and those of 20 mg/kg 22.5-75.9 micrograms/ml. 2. Serum half-lives of AZT were 3.5-6.6 hours in 0-3 day-old neonates, and 2.0-4.0 hours in neonates 4 day-old or older. 3. A dose response was evident between the 10 mg/kg administration group and the 20 mg/kg group. 4. Urinary recovery rates of AZT in the first 6 hours after administration ranged between 17.8 and 69.9%. 5. No clinical side effects were observed in the administration of AZT alone (6 cases), or in combination with ampicillin (9 cases). Thrombocytosis was observed in 1 case as an abnormal laboratory finding, but it returned to normal within 1 week after the completion of AZT administration. 6. AZT had a potent antimicrobial activity against Gram-negative aerobes and hardly induced beta-lactamase. Furthermore, side effects were not observed in this study. Therefore, AZT is considered to be useful for the treatment of urinary tract infections and other serious infections caused by Gram-negative pathogens even in the neonatal period.

[Antibacterial activity of norfloxacin on methicillin-resistant Staphylococcus aureus. Comparison with oral antibacterial agents].

Minimum inhibitory concentrations (MIC) of norfloxacin (NFLX) to 133 strains of methicillin-resistant Staphylococcus aureus (MRSA) isolated from clinical patients were investigated and compared with those of minocycline (MINO), erythromycin (EM), amoxicillin (AMPC), cefaclor (CCL) and fosfomycin (FOM). MIC90 of these drugs were 3.13 micrograms/ml with NFLX, 0.39 micrograms/ml with MINO, greater than 100 micrograms/ml with EM, 50 micrograms/ml with AMPC, greater than 100 micrograms/ml with CCL and greater than 100 micrograms/ml with CCL and greater than 100 micrograms/ml with FOM. MIC distribution patterns with 2 peaks were recognized with EM and FOM. Of 55 strains resistant to all of EM, AMPC, CCL and FOM, 50 and 54 strains were well susceptible to NFLX and MINO, respectively. The present investigation demonstrated relatively potent antibiotic effect of NFLX against MRSA. Considering the safety of NFLX to children which have been confirmed and reported separately, it can be concluded that NFLX is a useful oral antimicrobial drug in the treatment of children with MRSA infections.

[Studies on chemical analysis of mycotoxin (XXI). A rapid analytical method for aflatoxins by immunoaffinity column chromatography and high performance liquid chromatography].

An analytical method for aflatoxins using solvent extraction, affinity column (containing monoclonal antibodies against aflatoxins bound onto agarose) clean-up and high performance liquid chromatographic determination was applied to the analysis of aflatoxins in peanuts, pistachio nuts, white and black peppers and corn. Recoveries of aflatoxins B1, B2, G1 and G2 spiked to peanuts, pistachio nuts and corn at the level of 20 ppb were 77.4-81.4, 70.1-77.9 and 72.3-94.8%, respectively. In the case of white and black peppers, because the spiked aflatoxin recovery rate was low, further purification steps should be studied. The stability of the affinity column was good. This procedure is recommended as a rapid and reliable method for the analysis of aflatoxins in the three kinds of foods, peanuts, pistachio nuts and corn.

[Studies on chemical analysis of mycotoxin (XX). Chemical analysis of aflatoxins in corn and corn-products].

The investigation was carried out to analyze aflatoxins contaminated corn. 1) Methanol, chloroform and acetonitrile were used as the extraction solvents for aflatoxins added to corn. As the result, the method using acetonitrile was found to be effective to extract and detect aflatoxins. 2) The Rapid detection of aflatoxins was made possible by using the affinity column (containing monoclonal antibodies against aflatoxins bound onto agarose) and the mini-column. The detection-limit was 20 ppb of aflatoxins in samples.