Clinical evaluation of cefotaxime in the treatment of purulent meningitis in children.
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Biomedical subjects
Publications and source records attributed to Y Morikawa.
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Clinical trial of cefotiam was made in children and the following results were obtained. 1. Pharmacodynamic studies of the drug in CSF of experimental staphylococcal meningitis in rabbits showed a CSF/serum ratio of T 1/2 of 3.52, which was relatively high, but a percentage of CSF/serum ratio of AUC of only 3.42% up to 3 hours, suggesting a low efficiency of passage of the drug into CSF. 2. Blood concentrations of the drug were determined in children after an intravenous bolus injection of 20 mg/kg and were 46 mcg/ml (15 min.) and 26 mcg/ml (30 min.), T 1/2 being 40.8 min., Urinary recovery rate was 91.3% up to 4 hours in one patient and 61.9% up to 6 hours in another, respectively. 3. Thirteen patients with the following 14 episodes of infections were treated with cefotiam; urinary tract infection (5 cases), pneumonia (5), empyema (1), tonsillitis (1) and suspected sepsis (2). An overall efficacy rate was 100%, i. e., excellent in 12, good in 2 and no failure. No adverse reactions were clinically discernible and only laboratory abnormalities were transient or slight elevations of transaminase levels in 2 patients. 4. Based on the above results, it was concluded that cefotiam is a potent new antibiotic in the treatment of bacterial infections. Spectrum and antibacterial activity of the drug suggest that the drug particularly indicated for pneumonia.
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1. MIC of 6059-S against 92 strains of clinically isolated bacteria were measured. The compound was active against most of Gram-negative rods, but was not active against Staphylococcus aureus. 2. 20 mg/kg of 6059-S (newly synthesized oxacephem antibiotics) was administered to the pediatric patients and its blood concentration was measured by agar well method using E. coli 7437 as a test organism. 3. The mean blood concentrations were maximum at 15 minutes after intravenous one-bolus injection. Maximum levels were 94.5 mcg/ml in the patients of below 5 years old and 98.7 mcg/ml above 6 years old. Their half-life of the blood levels were 95.4 and 110.6 minutes respectively. 4. The mean blood concentrations were highest at the end of the infusion in the cases of 60 minutes drip injection. Maximum levels were 85.0 mcg/ml in the patients of below 5 years old and 64.8 mcg/ml above 6 years old. 5. Clinical efficacy of 6059-S in 6 cases pyelonephritis, 2 cases of sepsis, 1 case of meningitis, 1 case of intraperitoneal abscess, 9 cases pneumonia and 2 case of tonsillitis was 100%. In the case of urinary tract infection, 4 patients were treated successfully by the administration of 20 mg/kg/day of 6059-S. Other bacterial infections were treated with 55 to 200 mg/kg/day. 6. 100% of the causative organisms were eliminated by 6059-S. They were E. coli, Klebsiella pneumoniae, Serratia marcescens, H. influenzae and beta-Streptococcus. 7. No remarkable side effect was noticed during administration.
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Group B Streptococcus was isolated from the clinical materials of the patients examined in the Kobe Central Municipal Hospital, in 1974 to 1979. 1. Clinical isolates were all resistant to bacitracin. 2. Serotypes of 19 isolates were type III in 12 strains, Ia in 3, Ic in 2 and untypable in 2. 3. The MICs were determined to 15 antibiotics, and the results showed that penicillin G was the best and in the order of decreasing potency, cefotaxime, ampicillin, ceftizoxime and cefoperazone. 4. Compared with group A Streptococcus, the sensitivity of group B Streptococcus to penicillin G and ampicillin was inferior by 2 to 3 tubes. 5. Based on the above results, the significance of the cephalosporin antibiotic of the third generation, particularly cefotaxime, was evaluated in the treatment of infectious diseases of the newborn infants.
Fundamental and clinical studies were made on cefadroxil, a new oral cephalosporin, and the following results were obtained. (1) Antibacterial activity of the drug against S. aureus, S. epidermidis, E. coli, Klebsiella, Salmonella and P. mirabilis was almost equal to that of cephalexin. The MIC of indole positive Proteus. Enterobacter, Citrobacter, S. marcescens and P. aeruginosa to cefadroxil was higher than 100 microgram/ml in almost all strains. (2) Serum concentrations following an oral administration of 10.0 to 14.3 mg/kg of cefadroxil dry syrup was highest at 2 hours in 2 cases and 1 hour in 1 case, respectively, which were 13.4 to 17.1 microgram/ml, and 1.8 to 6.8 microgram/ml at 4 hours with an T 1/2 of 1.04 to 1.62 hours and apparently longer continuation of serum concentration than that of cephalexin. Urinary recovery rate was 75-96% up to 6 hours. (3) Fourteen patients, i.e., 6 with tonsillitis and 8 with urinary tract infection, were treated with a daily oral dose of 30-50 mg/kg divided in 4 doses except 1 case divided in 3 doses. The overall efficacy rate was 100%, i.e., excellent in 13, good in 1 and no failure. Causative organisms disappeared in all cases. (4) Adverse reactions, such as diarrhea and skin rash, were not noted at all and 1 case presented a mild elevation of GOT and GPT. (5) Taste and flavor of the drug was well palatable to children. (6) Based on the above results, it is concluded cefadroxil dry syrup is a new potent cephalosporin for oral use in the treatment of acute bacterial infection in children. Daily dose of 40 mg/kg in 3-4 divided doses appeared to be appropriate.
Pharmacokinetic differences between ampicillin and carbenicillin in the cerebrospinal fluid (CSF) were evaluated in experimental staphylococcal meningitis in rabbits after a single intravenous administration of 100 mg/kg dose of each drug. Half-lives (T 1/2) in CSF and CSF/serum ratios of T 1/2 were 52 minutes and 2.1 for ampicillin and 23 minutes and 1.3 for carbenicillin, respectively. These findings indicate that ampicillin is eliminated from CSF more slowly than carbenicillin. Penetration rates were calculated from CSF/serum ratios of area under the curve (AUC) and were 16.8% for ampicillin and 11.6% for carbenicillin, although the maximum concentration (Cmax) of carbenicillin in CSF was twice as high as that of ampicillin. Thus the penetration rate appeared to be influenced more by T 1/2 in CSF than by Cmax. Cmax in CSF was obtained at 15 minutes for carbenicillin and 30 minutes for ampicillin. As to carbenicillin there were considerable individual variations in CSF levels. The above observations suggest that T 1/2 and AUC in CSF are important parameters when evaluating the usefulness of an antibiotic in the treatment of bacterial meningitis.
Fundamental and clinical evaluations were made on cefoxitin, a new cephamycin antibiotic, and the following results were obtained. 1) MIC of the drug to clinical isolates was determined and was higher than that of cefazolin to Gram-positive bacilli. Among Gram-negative rods, the drug showed a sufficient antibacterial activity even to cefazolin-resistant strains. However, the MIC of cefoxitin to cefazolin-sensitive strains tended to be higher than that of cefazolin. 2) As to the passage of cefoxitin in experimental staphylococcal meningitis in rabbits, a percentage of CSF/serum ratio of AUC was 10.7% up to 3 hours and CSF/serum ratio of T1/2 was 1.78 of which value was an intermediate between those of ampicillin and cefazolin. There were, however, larger individual differences. 3) Blood concentrations and urinary recovery rates were determined in 2 children. In 1 patient, in whom the drug was given intravenously at a dose of 25 mg/kg, a blood concentration after 30 minutes was 50 microgram/ml, T1/2 was 57.2 minutes. This patient, however, showed a slight renal dysfunction. In another patient, who received an intravenous injection of 12.5 mg/kg, a 30 minutes blood concentration was 14.6 microgram/ml and T1/2 was 31.8 minutes. Urinary recovery rates up to 6 hours were 85.8% and 73.5%, respectively. 4) Thirty patients with the following bacterial infections were treated with cefoxitin, i.e., urinary tract infection (24 cases), respiratory tract infection (4 cases), each one case of peritonitis and suspected sepsis. An overall efficacy rate was 93.3%, i.e., excellent in 13 cases, good in 15, and failure in 2. Disappearance rate of the causative organism of the 23 clinical isolates was 87.0%, i.e., that the causative organism disappeared in 20 strains, reduced in 1 and persisted in 2. 5) Based on the above results, it was concluded that cefoxitin is a potent new antibiotic in bacterial infections in children, particularly respiratory and urinary tract infections. The optimal recommended dose will be about 25 mg/kg which should be given 3-4 times daily intravenously or by drip infusion.
Cross-sectional echocardiography has enabled us to demonstrate foetal cardiac structures, however, only a few studies have been reported. This report deals with a recently experienced foetus with double outlet right ventricle )DORV) diagnosed by this technique, confirmed by angiography and autopsy after birth. A 24-year-old pregnant woman with 24 weeks foetus underwent echocardiographic studies to evaluate the foetal heart because of its bradycardia. The cross-sectional echocardiogram showed a quite abnormal finding; i.e., two great arteries arose from the single ventricle which had coarse trabeculations. This finding suggested either DORV or single ventricle. The foetus was born at 40 weeks as a girl weighted 3040 g, and cyanosis was not observed. At one month of age, she began to experience increasing cyanosis by crying, and admitted to Keio Hospital for further examinations. She was performed catheterization and angiography, and was diagnosed as DORV. Cyanosis and dyspnea developed gradually and she died at the age of 2 months. Autopsy revealed DORV, polysplenia and dextrocardia.
Pharmacokinetic differences between a bolus and a 60 minutes continuous intravenous administration of 100 mg/kg dose of ampicillin in the cerebrospinal fluid (CSF) were evaluated in the rabbits with experimental staphylococcal meningitis. The maximum concentrations in CSF were 19.3 micrograms/ml for bolus injection and 7.24 micrograms/ml for 60 minutes continuous infusion. Half-lives (T1/2) in CSF and CSF/serum ratios of T1/2 were 29.9 minutes and 1.3 minutes for bolus injection and 48.1 minutes and 1.9 minutes for 60 minutes continuous infusion, respectively. These findings indicate that extremely high concentrations of short duration in serum are required to elevate the concentrations in CSF and the maintenance of certain concentrations in serum are required to keep concentrations above the therapeutic concentrations in CSF. The mean penetration rate derived from the CSF/serum ratios of AUC were 11.1% for bolus injection and 5.5% for 60 minutes continuous infusion. Thus bolus injection is considered to be superior to 60 minutes continuous infusion pharmacokinetically. Bacterial meningitis is one of the diseases in which therapeutic concentrations of antibiotics are difficult to attain at the the site of infections. Therefore, when an intravenous ampicillin is going to be used in the treatment of bacterial meningitis, bolus injection is preferred to 60 minutes continuous infusion.
Three human yolk sac tumors (TE, OE, and TT-1) were serially transplanted into nude mice. The histology of the transplanted tumors is moderately different from that of the original tumor; the transplants had mainly a tubular structure with an inconspicuous endodermal sinus structure due to a decreased mesenchymal element surrounding the vascular core. Ultrastructural features of the transplanted tumor cells, however, were identical to those of the original tumor. Immunochemical survey of the blood plasma of nude mice bearing these tumors demonstrated the production of adult type human plasma proteins including prealbumin, albumin (Alb), alpha 1-antitrypsin (alpha AT), transferrin (Tf), hemopexin, and alpha 1-fetoprotein (AFP). The types of adult plasma proteins that were produced varied, depending on the tumor line but were the same between serial passages within the same tumor line. The intracellular localization of AFP, alpha AT, Tf, and Alb was also investigated by immunoelectron microscopy. Plasma proteins of the adult type and AFP were localized mainly within the membrane systems of the endoplasmic reticulum and Golgi complex and occasionally on the microvilli. These results suggest that transplanted human yolk sac tumors have almost all of the protein-producing function possessed by their normal counterparts.
This is the first report on acetylcholine (Ach) quanititaion of the aganglionic colon by a chemical assay. Ach content in the colon of Hirschsprung's disease was measured by pyrolysis gas chromatography, which was found to be a simple, accurate, and reliable method. Microwave irradiation on the surgical resected specimens was performed before extraction procedure to abolish acetylcholinesterase (Ach-E) and cholineacetyltransferase (CAT) activity in the tissue. Ach content in the ganglionic colon was 8.51 +/- 3.15 nmole/g (n 5 in contrast to 23.79 +/- 14.17 nmole/g (n = 19) in the aganglionic segment of Hirschsprung's disease. The meaning of elevated Ach level in the aganglionic segment was discussed from the pathophysiologic standpoint.
In a case of Engelmann's disease in an 11-year-old Japanese boy the muscular changes were studied in detail. Muscle weakness was maximal about the pelvic girdle. Muscle biopsy showed the selective atrophy of type II fibres, and no degenerative change could be seen histologically, histochemically, or electron-microscopically. Although the distribution of muscular weakness in Engelmann's disease is similar to that of a progressive muscular dystrophy, the disease does not seem to be a myopathy.
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A small rapid phase (1st phase) was distinguished from a concomitant phase (2nd phase) in contraction of guinea-pig vas deferens. The vas deferens 4 days after denervtion exhibited supersensitivity to stimulants. The supersensitivity in the 2nd phase of contraction was nonspecific, but that in the 1st phase was specific to muscarinic cholinergic agonists. The increase in sensitivity resulted in a shift of the dose-response curve to lower concentrations without significant change in the maximal response. Muscarinic cholinergic receptors in the vas deferens, determined by measuring binding of [3H]quinuclidinyl benzilate, changed after denervation. The maximal binding sites increased from 115 to 165 fmol/mg of protein with no significant change in the dissociation constant. The affinity of the receptor for agonist also did not change significantly. Studies on [3H]WB4101 binding indicated no significant change in alpha adrenergic receptors after denervation. Thus, specific supersensitivity of the cholinergic mechanism mediated by muscarinic acetylcholine receptors occurred after denervation of guinea-pig vas deferens. This increased sensitivity is discussed in relation to the amount of receptor.
Clinical evaluation was made on cefoperazone (CPZ) and the following conclusions were obtained. (1) Serum concentrations of the drug after a one-shot intravenous injection of 22.2 mg/kg were 77 mcg/ml (30 minutes), 50 mcg/ml (1 hour) and 8.9 mcg/ml (4 hours) and T 1/2 of serum concentration was 68.5 minutes. A 35-day-old female with obstructive jaundice associated with choledochal cyst was given by a 30-minute drip infusion of 26.8 mg/kg of the drug. Serum concentration was 90 mcg/ml at the end of infusion, slowly declined thereafter, and was 47.5 mcg/ml at 6 hours. Its T 1/2 was 395 minutes. A patient with pyelonephritis complicated with right hydronephrosis was similarly treated with 24.4 mg/kg. T 1/2 of serum concentration was not prolonged, i.e., 82.1 minutes, but urinary recovery rate up to 6 hours was decreased to 15.9%. (2) Five patients, including three with pyelonephritis (causative organism: K. pneumoniae 2 and P. aeruginosa 1) and each one patient with pneumonia (unknown) and with postoperative infection (S. faecalis), respectively, were treated with 66.7 approximately 96.8 mg/kg/day of CPZ in 3 divided doses for 5 approximately 12 days either by one-shot intravenous or by 30 approximately 60-minute drip infusion. An overall efficacy rate was excellent in 3 and good in 2, and there was no failure. Causative organisms disappeared in all cases. (3) Although one patient was excluded from the study because the diagnosis was supposed to be viral pneumonia, all six patients who were given CPZ did not exhibit any adverse reactions except for mild eosinophilia in two instances. (4) The foregoing results as well as the review of the literature clearly indicate the effectiveness of CPZ in the treatment of bacterial infections in children.
Clinical evaluation of cefmetazole were made in the treatment of bacterial infections in the newborn infants and the following results were obtained. 1) Five infants, 7 approximately 58 days of age, received a single intravenous one-shot injection of 22.2 approximately 24.5 mg/kg dose of cefmetazole, and blood concentrations were determined. The average level was 62.6 micrograms/ml (30 minutes), 46.3 micrograms/ml (1 hour), 26.8 micrograms/ml (2 hours), 8.7 micrograms/ml (4 hours) and 2.4 micrograms/ml (6 hours), and T 1/2 was 87.7 minutes. Almost similar values were obtained when the drug was given by a 30-minute drip infusion and sufficiently exceeded the MIC to the bacteria to which cefmetazole was indicated. 2) In two patients, who had been operated for choledochal cyst and received an intravenous drip infusion of the drug, the persistence of the blood concentration was remarkably long, T 1/2 being 192 and 222 minutes, respectively. This problem still remains to be elucidated. 3) The following 22 patients were treated with an intravenous one-shot or drip infusion of cefmetazole, i.e., 45.6 to 107.1 mg/kg divided in 2 approximately 3 doses; 14 patients aged 1 to 21 days, 2 aged 1 to less than 2 months, 3 aged 2 to less than 3 months and 3 aged older than 3 months. However, in purulent meningitis, larger dose was given intravenously 6 times daily. Diseases included sepsis (4 cases), purulent meningitis (3), peritonitis (1) SSS syndrome (3), subcutaneous abscess (2), urinary tract infection (8) and Salmonella enteritis (1), and their causative organisms were E. coli (13 strains), K. pneumoniae (1), S. typhimurium (1), S. aureus (6) and group B Streptococcus (1). Overall efficacy rate in 22 cases was 90.9%. i.e., excellent in 11, good in 9 and failure in 2. Two cases of failure were a patient with peritonitis and visceral eventration due to umbilical hernia and a patient with a chromosomal aberration and urinary tract infection caused by E. coli. Reasons for such a treatment failure appeared to reside in host factors. 4) Adverse reactions included each one case of skin rash and diaper rash, 3 cases of eosinophilia and 5 cases of elevation of transaminase levels, all of which were mild and transient. 5) Based on the above results, cefmetazole is considered to be a potent new antibiotic which should be indicated as the first choice drug in the treatment of neonatal bacterial infections. The recommended dosage is as follows: 50 mg/kg given intravenously 6 times daily for bacterial meningitis and 20 approximately 25 mg/kg intravenously or by a drip infusion 2 to 3 times daily for other infections.