Evaluation of cefpiramide in pediatrics

Fundamental and clinical trials were carried out with cefpiramide (CPM) in pediatric infections. Results were as follows. CPM has a broad spectrum of activity against both Gram-positive and -negative microorganisms, including Pseudomonas. Half-lives of CPM were more prolonged than any others that have ever been reported on cephalosporin derivatives. The mean half-lives in the blood after infection were 4.76 hours and 4.14 hours, when the doses were 10 mg/kg and 20 mg/kg, respectively. The average recovery rates in the urine between 0 and 8 hours were 17.1% and 24.7%, when the intravenous doses were 10 mg/kg and 20 mg/kg, respectively. Thirty-two pediatric patients received CPM in doses ranging from 31.9 to 88.2 mg/kg divided mainly 2 times a day. They were respiratory tract infection in 23, urinary tract infection in 8, and SSSS in 1. The rate of satisfactory clinical response was 90.6%. Clinical side effect observed were mild diarrhea in 7 cases. Slight elevation of GOT and GPT were observed in 3 cases. All were considered to be minor.     

Study on cefodizime, a new cephem antibiotic, in the field of pediatrics

Experimental and clinical study of cefodizime (CDZM, THR-221), a newly developed cephem antibiotic, was done in the field of pediatrics and the results obtained are summarized as follows: 1. Serum levels and urine excretion were examined after 60-minute drip infusion of CDZM at a dose level of 10 mg/kg to 1 patient, at 20 mg/kg to 4 and at 40 mg/kg to 1. Peak levels in serum were 66.3 micrograms/ml for the 10 mg/kg dose occurring 1 hours after the dose, 118.1 micrograms/ml (mean) for 20 mg/kg, 259.2 micrograms/ml for 40 mg/kg, thus a dose-response was observed. T 1/2's (beta phase) were between 1.17 and 1.69 hours. Urinary recovery rates of the drug were between 71.5% and 98.0% in the first 8 hours after administration. 2. The concentration in the cerebrospinal fluid was 0.76 microgram/ml and the serum level was 380.67 micrograms/ml at 15 minutes after intravenous administration of 433 mg of CDZM to a patient with purulent meningitis. 3. The clinical efficacy rate was 95.2% in a total of 21 cases, i.e., 1 purulent meningitis, 10 respiratory tract infection, 3 whooping cough, 5 urinary tract infection, 1 purulent infection of soft tissues and 1 acute thyroiditis. Diarrhea occurred in 1 case as adverse reactions. Abnormal changes in laboratory test results occurred as 1 case each of slightly elevated GOT.GPT and GOT.     

Phase I study of E1040, a new parenteral cephem antibiotic

The safety and pharmacokinetics of E1040, a new injectable cephem antibiotic, were evaluated in healthy volunteers. In single-dose studies, 125, 250, 500, 1000 and 2000 mg of E1040 were administered by I.V. infusion over 1 hour. Results of 5 minutes I.V. infusions of 500, 1000 and 2000 mg of the drug were also studied. Plasma concentration-time profiles were well suited to a two-compartment open model. The half-life of elimination from plasma was 1.85 +/- 0.16 hours, and the Cmax and AUC paralleled the doses given. The mean urinary recovery within the first 24 hours was 85.7 +/- 6.43% of the dose. In a multiple-dose study, 2000 mg of E1040 (I.V. over 1 hour) was administered every 12 hours (total 9 times) and no abnormal accumulation of the drug in plasma was observed. There were no significant differences in plasma levels or in urinary recoveries between single- and multiple-dose regimens. There were no subjective or objective abnormal findings definitely attributable to the drug except that one subject given 250 mg over 1 hour reported diarrhea, and another complained of nausea during the infusion of 2000 mg over 5 minutes. From these results E1040 was concluded to be safe and well tolerated.     

Clinical evaluation of cefpiramide in pediatrics

Clinical studies of cefpiramide (CPM), a newly developed cephem antibiotic, were performed in 10 children with respiratory tract infection in 4 cases, acute enteritis in 2 cases and urinary tract infection in 4 cases aged from 2 months to 10 years and 4 months. CPM was intravenously given to patients at doses of 16 approximately 58 mg/kg/day divided into 3 times for 3 approximately 22 days. Clinical effects were excellent in 6, good in 3 and fair in 1. Bacteriologically, 3 strains of pathogenic organisms (Salmonella C2 group, E. coli and S. faecalis) isolated from the patients were eradicated with the treatment of CPM. No side effect was observed.     

Cefuzonam, a new cephem antibiotic in the field of pediatrics. Concentrations in serum and clinical efficacy

A new cephem antibiotic, cefuzonam (L-105, CZON) was studied for its concentrations in serum and clinical efficacy in the field of pediatrics. To examine the concentration of CZON in serum, 20 mg/kg of CZON was administered by intravenous drip infusion to a male patient of 6 years and 7 months. The half-life of the drug in serum was 0.97 hour after administration. CZON was administered to 7 cases of pediatric infections, and clinical result were "excellent" in 4, "good" in 1, "poor" in 2: the efficacy rate was 71.4% or 5 cases out of 7. As an adverse reaction, eruption was observed in 1 patient.     

Results of clinical application of cefpiramide in pediatrics

After the intravenous injection of cefpiramide (CPM) at a dose of 10 mg/kg to 2 children, the average blood levels of CPM were 77.7 micrograms/ml at 15 minutes, 64.6 micrograms/ml at 30 minutes, 41.9 micrograms/ml at 1 hour, 31.9 micrograms/ml at 2 hours, 10.7 micrograms/ml at 4 hours and 3.28 micrograms/ml at 12 hours. The half-lives were 3.0 hours and 5.8 hours. When CPM was given to 22 pediatric patients with mainly acute respiratory tract infection at doses of 20 approximately less than 50 mg/kg/day divided into 2 times by intravenous injection (12 cases) and drip-infusion (10 cases) for 2 approximately 3 days (10 cases) or 4 approximately 6 days (12 cases), the effective rate was 90.9%. No side effects were observed except slight increase of eosinophil in 1 case slight elevation of GOT in 1 case. It was concluded that CPM is a useful drug for the treatment of infection in pediatric field.     

Experimental and clinical evaluation of cefpiramide in pediatrics

Fundamental and clinical studies on cefpiramide (CPM), a new semisynthetic cephalosporin, were made and the following results were obtained. The antibacterial activities of CPM against clinical isolates were almost similar to those of conventional cephems except for Pseudomonas aeruginosa. The antibacterial activity of CPM against P. aeruginosa was excellent and superior than those of the others. Ten or twenty mg/kg of CPM was given intravenously at one shot to 11 cases. The mean serum levels of CPM reached 231 micrograms/ml at 15 minutes, 119 micrograms/ml at 30 minutes, 88 micrograms/ml at 1 hour, 65 micrograms/ml at 2 hours and 33 micrograms/ml at 6 hours after administration at a single dose of 10 mg/kg, respectively with the half-life of 3.42 hours. In case of 20 mg/kg, the mean serum levels attained 306 micrograms/ml at 15 minutes, 245 micrograms/ml at 30 minutes, 160 micrograms/ml at 1 hour, 118 micrograms/ml at 2 hours and 66 micrograms/ml at 6 hours respectively after administration with the half-life of 5.20 hours. CPM was given intravenously to 12 patients with various bacterial infections. The clinical effects were excellent in 5 cases, good in 6 cases and poor in 1 case and the effective rate was 92%. No side effect was observed in all cases.     

Susceptibility of clinical isolates in pediatrics to cefpiramide

Cefpiramide (CPM, SM-1652) had broad-spectrum antibacterial activities against most of clinically isolated organisms to which are paid attention as pathogenic organism in the field of pediatrics. Antibacterial activities of CPM against Staphylococcus aureus, Streptococcus pyogenes, Haemophilus influenzae, Bordetella pertussis and Proteus mirabilis were almost the same as those of cefoperazone (CPZ). Antibacterial activities of CPM against Escherichia coli and Klebsiella pneumoniae were somewhat weaker than those of CPZ, but antibacterial activity of CPM against Pseudomonas aeruginosa was rather stronger than that of CPZ and almost the same as that of cefsulodin. Antibacterial activity of CPM has a tendency to decrease in beta-lactamase (PCase type) producing S. aureus, E. coli, K. pneumoniae, H. Influenzae, etc. It is suggestive that the determination of not only the antibacterial activity of CPM against pathogenic organisms but also the beta-lactamase producing activity of them is important on the occasion of clinical use of CPM.     

Clinical evaluation of a new oral cephem, cefdinir, in children

Cefdinir (CFDN, FK482) was evaluated for its safety, efficacy and pharmacokinetics in 28 children. CFDN was effective in 100% of 22 evaluable cases with respiratory, middle ear, urinary or soft tissue infections. From the clinical response, adverse effects and the pharmacokinetic results, daily dose of 9-18 mg/kg, administered in 3 divided portions is suggested. Increase of dose will be associated with increase of gastrointestinal side effects. The data suggest that CFDN is safe and effective when used in children with infections caused by susceptible bacteria including Staphylococcus aureus.     

Novelties in the field of parenteral cephem antibacterials since 1993

There is still considerable interest in cephem antibacterial agents. In fact, there are a significant number of patents submitted for this antibacterial class. All the new cephem derivatives, independent of which group they belong to (III to V), possess a 2-amino-5-thiazolyl or a 5-amino-2-thiadiazolyl ring with an oxime group (at position 7 of the cephem nucleus). At position 3, they have a C-3' quaternary ammonium moiety. Research has focused on the following structural modifications: the nature of the oxime residues and the charged azolium heterocycle, and the addition of the vinylogous chain. The aim of researchers is to increase the overall activity of these compounds against Gram-negative bacilli, including against isolates producing type 1 beta-lactamases or extended spectrum beta-lactamases (Enterobacteriaceae). Non-fermentative Gram-negative bacilli are now included in the first screening process, in addition to Pseudomonas aeruginosa. Extensive research is ongoing with the aim of solving the MRSA problem. New promising entities have been reported.     

Study on a new cephamycin preparation cefminox in the field of pediatrics

Cefminox (CMNX, MT-141) was studied both fundamentally and clinically in the field of pediatrics with following results. The MIC of CMNX for Bordetella pertussis was 0.10 micrograms/ml in inoculum size 10(6) cells/ml. Following administration of 10 and 20 mg/kg of CMNX as drip infusion over 1 hour, the blood levels of the drug were 49.0 +/- 18.1 and 69.1 micrograms/ml at completion of infusion, 28.8 +/- 7.7 and 61.6 micrograms/ml at 1.5 hours, 23.6 +/- 9.3 and 44.1 +/- 3.8 micrograms/ml at 2 hours and 1.4 +/- 1.4 and 4.0 +/- 0.6 micrograms/ml at 7 hours, with T1/2 of 1.03 and 1.41 +/- 0.03 hours, respectively. Within the first 7 hours after administration, 61.4 +/- 8.2 and 55.9 +/- 0.8% of the drug dosed were excreted at active form in urine. In child with encephalitis, drug considered to be good as a cephem antibiotic was achieved in the cerebrospinal fluid (the ratio of the level in the cerebrospinal fluid to that in the serum was 7.3%). In addition, in the pus in empyema also high level was reached (its ratio against blood level was 53%). In the treatment of 31 cases of acute infections of pediatric field including upper and lower airway infections, empyema, whooping cough, acute urinary tract infections and phlegmon, CMNX was administered intravenously either as one shot injection as drip infusion. The clinical results obtained were rated as good or more in 93% of the cases and as fair or more in 100% of the cases. The main dosage of CMNX in these cases was about 60 to 70 mg/kg per day in 2 or 3 divided doses. S. aureus, S. pyogenes, S. pneumoniae, H. influenzae and ABPC resistant strain of E. coli demonstrated in various materials could be eradicated after intravenous injection of CMNX. CMNX was administrated for a period of 2 to 16 days to a total amount of 1.5 to 26.5 g. In none of these cases side effects developed nor any abnormality was revealed by hematological findings or results of renal or liver function.     

Experimental efficacy and pharmacokinetic properties of cefpiramide, a new cephalosporin

The in vivo therapeutic efficacy of cefpiramide was investigated and compared with that of cefoperazone. Cefpiramide was more potent than cefoperazone against infections produced by both beta-lactamase-producing and non-beta-lactamase-producing S. aureus. The protective activity of cefpiramide against experimental infections with selected members of Enterobacteriaceae was lower than that of cefoperazone. Against carbenicillin-resistant P. aeruginosa infections, cefpiramide was as active as gentamicin and aztreonam and three times more potent than cefoperazone, cefotaxime and piperacillin. The pharmacokinetic properties of cefpiramide in mice and rats were superior to those of cefotaxime and cefoperazone. The peak serum concentrations of cefpiramide, administered subcutaneously at a dose of 50 mg/kg, were 76 micrograms/ml in mice and 174 micrograms/ml in rats and the corresponding serum half-lives of cefpiramide were 87 min and 49 min in mice and rats respectively.     

Clinical evaluation of a new oral cephem, cefprozil in children]

Cefprozil (CFPZ, BMY-28100) was evaluated for its efficacy, safety and pharmacokinetics in children. CFPZ was effective against streptococcal pharyngitis, pneumococcal lower respiratory tract infections, staphylococcal skin infections and Escherichia coli urinary tract infections, but was less effective against lower respiratory tract infections and otitis media due to Haemophilus influenzae. No adverse reactions were encountered in 46 cases treated with CFPZ. With a premeal administration of 7.5 mg/kg, the Cmax was approximately 3.2 micrograms/ml and the T 1/2 beta was 1.4 hours. From the present study, CFPZ appears to be safe and effective against community-acquired childhood infections.     

Clinical evaluation of a new oral cephem, cefpodoxime proxetil in children

Cefpodoxime proxetil (CPDX-PR, CS-807) was evaluated for its efficacy, safety and pharmacokinetics in children. CPDX-PR was effective in 93.6% of 47 cases with respiratory tract, middle ear, skin or urinary tract infections. Twice or 3 times daily administration of 3 mg/kg each was sufficient to treat streptococcal pharyngitis and Haemophilus influenzae infections. No severe adverse reaction was encountered in 52 cases treated with CPDX-PR. The serum half-life was approximately 2.17 +/- 0.24 hours after oral administration.     

General pharmacology of T-2588, a new oral cephem antibiotic

A new oral cephem antibiotic, T-2588, the pivaloyloxymethyl ester of (+)-(6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3- [(5-methyl-2H-tetrazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2. 0]oct-2-ene-2-carboxylic acid (T-2525), is mainly absorbed from the intestinal tract and biotransformed to T-2525 thereafter. General pharmacological activities of T-2588 were studied and following results were obtained. On the central nervous system, T-2588 did not show any effects at oral doses of 500-2,000 mg/kg and T-2525 produced only a slight elevation of body temperature in rabbits without any other effects at an intravenous dose of 500 mg/kg. On the respiratory and cardiovascular systems, T-2525 caused a slight hypotension and increased both respiratory rate and femoral blood flow, but no changes were observed in heart rate and electrocardiogram in dogs at an intravenous dose of 500 mg/kg. The T-2525 exerted no significant influence on blood pressure response to isoproterenol, acetylcholine or histamine, but showed a slight tendency to decrease pressor response to adrenaline in dogs at intravenous doses of 100-500 mg/kg. For the renal function in rats, T-2588 had no effects on urine volume, electrolytes and PSP excretion at oral doses of 500-2,000 mg/kg. Intravenous administration of T-2525 caused an increase of sodium excretion at 500 mg/kg and dose-dependent increases of PSP excretion at 20-500 mg/kg. Hematological studies revealed that both T-2588 at oral doses of 500-2,000 mg/kg and T-2525 at intravenous doses of 100-500 mg/kg had no effects on bleeding time in mice, blood coagulation and platelet aggregation in rats. The T-2588 exerted no effect on the gastrointestinal system in rats or mice and had no antiinflammatory activity in rats at oral doses of 500-2,000 mg/kg. The T-2525 scarcely affected the motilities of isolated smooth muscle preparations in experimental animals including stomach, ileum, colon, uterus, vas deferens and trachea at a concentration as high as 10(-3) g/ml. The T-2525 increased bile secretion in rats at intravenous doses of 100-500 mg/kg. The T-2525 slightly decreased the twitch tension of musculus gastrocnemius induced by electrical stimulation in rats at an intravenous dose of 500 mg/kg. These results indicate that T-2588 is a pharmacologically inactive antibiotic.     

Clinical studies on SM-4300, a new human gammaglobulin preparation for intravenous use in pediatrics

Six cases of severe infections in pediatrics, which showed no or insufficient responses to treatment with antibiotics, were treated with additional intravenous infusion of SM-4300. Results were as follows. Three cases of bacterial infections with high fever, showing no response to chemotherapy, were treated with SM-4300, (68-135 mg/kg). Administration of SM-4300 resulted in defervescence, decreasing pain and swelling and showing a trend for improvement in CRP values. Administrations of SM-4300 (61-100 mg/kg) against pleurisy caused by Mycoplasma were effective in defervescence and improvement in chest findings. Clinical effects of SM-4300 were excellent in 2 cases, good in 3 and fair in 1. In this study, no clinical side reactions nor abnormal laboratory values in blood, liver or renal functions were observed.     

Fundamental and clinical studies in pediatrics on PC-904, a penicillin with broad spectrum newly developed in Japan (author's transl)

Fundamental and clinical studies of PC-904, a newly developed penicillin with a broad spectrum, were performed and the following results were obtained. (1) The serum levels of PC-904 after 1.5 hours drip infusion reached the peak at 1 hour or at the end of the infusion and the detectable levels of PC-904 were maintained up to 2 or 3 hours after the end of the infusion. (2) The urinary excretion rates up to 6 hours after the onset of the infusion were 19.2 approximately 25.5%. (3) Forty-one patients were treated with PC-904 and the majority of the diseases were acute respiratory infections. The treatment by the drip infusion of 50 approximately 100 mg/kg/day resulted in good responses to whooping cough, and lacunar tonsillitis, lymphadenitis and staphylococcal scald skin syndrome resistant to the treatment by ampicillin and cephalexin. The satisfactory results were also obtained by the treatment of almost the same dosage in the patients with acute bronchitis, bronchopneumonia and measles pneumonia. (4) Staphylococcus aureus and Klebsiella pneumoniae were isolated from the sputum culture of the patients with bronchopneumonia and they responded well to the treatment with PC-904. (5) The drip infusion of 60 approximately 70 mg/kg/day for 5 approximately 6 days was shown to be useful in the treatment of urinary tract infection of which the causative organism was E. coli. (6) No side effects were observed except rubella-like eruption in one case. (7) Clinical evaluation was examined in all cases except one patient of which the medication was withdrawn due to eruption, and the overall clinical efficacy was excellent or good in all of 40 cases.     

Clinical evaluation of a new oral cephalosporin, cefprozil, in pediatrics]

Cefprozil (CFPZ, BMY-28100), a new oral cephalosporin, was evaluated for its antibacterial activity and clinical efficacy. Thirty-four patients were treated with 7.7-36.2 mg/kg per day of CFPZ divided into 3 times. A total of 33 patients including 3 with acute pneumonia, 2 with acute bronchitis, 17 with acute upper respiratory tract infections, 4 with urinary tract infections, 1 with suppurative lymphadenitis and 6 with other soft tissue infections were evaluated for clinical efficacy except for 1 patient whose general conditions were too serious to continue to be treated with orally medication. Clinical effects were excellent in 8 patients and good in 23 but 2 cases were excluded because they were suspected for viral infections, hence the overall efficacy rate was 100%. Bacteriological responses were confirmed on 6 (66.7%) strains which were eradicated by the treatment out of 9 strains identified. CFPZ showed stronger antibacterial activities than those of cefaclor. Side effects or abnormal laboratory test results were observed in 2 patients; nausea and pallor of face in 1 patient and an increase of eosinophil in 1. The above findings suggest that CFPZ is a safe and useful antibiotics for the treatment of bacterial infections in pediatric patients.