Clinical and pharmacokinetic studies of gentamicin in intravenous drip infusion to children

Eighteen children with urinary tract infection were treated with intravenous drip infusion of gentamicin (GM), and clinical efficacy and pharmacokinetics were studied. Ages of the patients ranged from 2 months to 12 years. Doses of GM ranged 1.0 to 2.5 mg/kg every 8 to 12 hours, and treatment continued for 4 to 10 days. Among 18 patients treated, clinical results were excellent in 12, and good in 6. Values of BUN and creatinine remained within normal range in all patients during and after the GM treatment. One child had an eosinophilia. There were no cases that showed signs and symptoms of oto- and nephrotoxicity. Twenty eight time-serum level curves were studied in 16 patients during and after intravenous infusion of GM over 30 minutes. Doses were 1.0 mg/kg in 4, 1.9-2.0 mg/kg in 14, and 2.2-2.5 mg/kg in 10. Peak serum levels at 30 minutes after the start of infusion were 2.66-7.38 micrograms/ml (average 5.45 micrograms/ml) in cases receiving 1.0 mg/kg, 4.67-10.8 micrograms/ml (7.26 micrograms/ml) in 1.9-2.0 mg/kg, and 6.16-16.5 micrograms/ml (8.86 micrograms/ml) in 2.2-2.5 mg/kg. Elimination half-lives were 1.75-2.48 hours (average 2.10 hours) in cases with ages less than 1 year, 1.58-2.58 hours (2.01 hours) with 1 to 6 years, and 1.20-3.07 hours (1.66 hours) with 7 to 12 years who were given doses of 1.9-2.5 mg/kg. There were no significant differences in pharmacokinetic parameters between first and last administration in these patients, suggesting that no accumulation occurred with above mentioned doses. Urinary recovery of GM ranged from 21.9 to 99.2 percent (average 62.48%) within 6.5 hours after the initiation of drip infusion.     

Clinical studies on aztreonam following intravenous drip infusion

Aztreonam (AZT), a new synthetic monocyclic beta-lactam antibiotic, which is resistant to beta-lactamase and has a strong and specific activity against aerobic Gram-negative bacteria including Pseudomonas aeruginosa. The patients of 13 cases with localized peritonitis due to acute appendicitis, 3 cases with panperitonitis (1 case with perforative appendicitis, 1 with acute cholecystitis and 1 with pancreatic necrosis) and 4 cases with skin and soft tissue infection (anal fistula and abdominal abscess etc.) were treated by AZT. AZT was administered in a dose of 1 g twice a day by intravenous drip infusion using 100 ml-volume bottle preparation with saline for 4 to 10 days. Clinical efficacy was rated excellent in 2 cases, good in 16 cases, fair in 1 case and poor in 1 case (efficacy rate 90.0%). Adverse effects were small skin rash in 1 case, and increased GOT and GPT in 1 case. No adverse effect was recognized in other cases. Therefore, AZT appears to be very useful drug when used for chemotherapy of infectious diseases in surgery.     

Study on the serum concentrations of gentamicin after intravenous drip infusion

Serum concentrations of gentamicin (GM) were monitored after intravenous drip infusion of 60 mg over 30 minutes, 1 hour and 2 hours. These concentrations were compared with those after intramuscular injection. The mean peak serum concentration obtained at 30 minutes after intramuscular injection (5.09 micrograms/ml) and those obtained at the end of intravenous drip infusion (5.17--6.66 micrograms/ml) were comparable. Serum concentrations decreased to less than 2.0 micrograms/ml at 6 to 8 hours after injection or infusion in all cases except 1 with less body weight than others. Pharmacokinetic analysis showed that the T1/2 of GM ranged from 2.49 to 4.33 hours and that the AUC ranged from 19.66 to 27.09 hr X micrograms/ml. Results obtained in this study suggested that the usefulness of intravenous drip infusion over the time from 30 minutes to 2 hours is equal to that of intramuscular injection in the GM therapy.     

Clinical studies of intravenous drip infusion of micronomicin. Urinary tract infections

There is a growing tendency that aminoglycosides are used by intravenous drip infusion. Micronomicin sulfate (MCR) is a new aminoglycoside antibiotic and its mild nephrotoxicity and ototoxicity demonstrated in animals set us to perform clinical studies, in which 22 institutions in Japan used this antibiotic by intravenous drip infusion for the treatment of urinary tract infections and reached the following conclusions: The response rate in complicated urinary tract infections was 60.6% when daily 240 mg was administered in 2 doses and 52.9% when daily 360 mg was administered in 2 doses or 3 doses. Intravenous drip infusion of daily 240 to 360 mg of MCR did not present safety problems. Intravenous drip infusion of MCR is therefore considered to be of clinical interests in urinary tract infections.     

Clinical studies of intravenous drip infusion of micronomicin. 1. Absorption and excretion

Pharmacokinetics of MCR administered by 1 hour intravenous drip infusion were studied in healthy volunteers by two-compartment model. In 120 mg-dosage group (n = 3) studies were made by single administration, and in 60 mg-dosage group (n = 4) were administered twice daily and continued until a total of 9 doses. Results: When MCR was administered in a 60 mg dosage, its Cmax was 4.3 +/- 0.3 micrograms/ml (mean +/- S.D.) after the 1st dose and 3.7 +/- 0.4 micrograms/ml after the 9th dose, while it was 8.8 +/- 1.0 micrograms/ml when the dosage was 120 mg. It should be noted that in the case of repeated dosing with 60 mg, serum levels just before administration were always below the analytical limit. The mean of T 1/2 was 1.69 +/- 0.14 hours, remaining stable at all determination. The kinetic parameters that showed different values between determinations performed after the 1st and 9th 60 mg doses were V1 (0.107 vs 0.164 L/kg) and Kel (1.02 vs 0.68 hr-1). This was also the case with comparison of 2 different dosage groups (60 mg 1st vs 120 mg; V1: 0.107 vs 0.135 L/kg, Kel: 1.02 vs 0.72 hr-1). There was no evidence indicative of side effect of MCR. Discussion: The above results demonstrated that Cmax and other kinetic parameters were little influenced by whether MCR was administered by intravenous drip infusion or by intramuscular injection. There was a little larger difference in AUC between those 2 routes of administration but the differences seemed negligible when the same dosage was used. Pharmacokinetic studies are to be continued in subjects whose renal function is impaired in different ways to establish the optimum dosage regimen for MCR.     

Clinical evaluation of amikacin by intravenous drip infusion for infections in the field of internal medicine

Amikacin (AMK) by intravenous drip infusion was given to patients with infections in the field of internal medicine and the results were followings: AMK was administered to 19 patients. Diagnosis included sepsis or suspected sepsis (11 cases), pneumonia (2 cases), chronic respiratory tract infections (3 cases) and urinary tract infections (3 cases). Underlying disease included hematologic disease (13 cases), lung fibrosis (1 case), chronic respiratory insufficiency (1 case), diabetes mellitus (1 case), hepatic coma and bronchial asthma (1 case) and prostatic hypertrophy (1 case). Nineteen episodes responded to single therapy (2 cases) or combined therapy with other antibiotics (17 cases). AMK by intravenous drip infusion (dissolved in not less than 100 ml of saline or glucose) was administered at the dose of 200 mg/day to 600 mg/day divided into 2 or 3 times, over 1 hour to 2 hours. The mean duration of therapy was 10 days and the mean total dose was 4.3 g. Clinical effects: Excellent in 7 cases, good in 7 cases, fair in 3 cases and poor in 2 cases, and efficacy rate was 74%. Bacteriological effects: Disappeared in 3 cases, partly disappeared and unchanged in 3 cases, superinfection in 1 case and newly appeared in 1 case. Four strains out of 7 cases of which were detected the causative bacteria were disappeared. GM resistant bacteria (S. marcescens in 2 strains and C. diversus in 1 strain) were disappeared by the administration of AMK, also some clinical symptoms and signs were improved. No side effects and no abnormalities in laboratory findings were noted in any cases attributed to AMK. In conclusion, high efficacy rate was obtained without any side effects, intravenous drip infusion of AMK seemed to be useful for infections in patients with bleeding tendency (e.g. leukemia) or malignant disease.     

Clinical evaluation of astromicin by intravenous drip infusion. Report I. Bacterial infections in the field of internal medicine

Intravenous drip infusion of a new aminoglycoside agent, astromicin (ASTM), was used against various infections in the field of internal medicine, and its clinical efficacy and safety were studied. Clinical effects were evaluated in 105 among 111 patients administered with ASTM. Almost all the patients were given 200 mg of ASTM twice a day by intravenous drip infusion for 60 minutes. Among 105 cases, clinical effects of ASTM were excellent in 15, good in 56, fair in 10 and poor in 24. The number of cases who were judged as excellent or good was 71, and the efficacy rate was 67.6%. Efficacy rates classified by diseases were as follows; 80% (4/5 cases) in sepsis, 55.6% (5/9 cases) in urinary tract infections, and 68.1 (62/91 cases) in respiratory tract infections (RTI). In 91 cases with RTI, clinical effects of ASTM were excellent in 14, good in 48, fair in 9 and poor in 20. The efficacy rates classified by diseases of RTI were 77.3% (34/44 cases) in pulmonary parenchyma infection and 59.6% (28/47 cases) in chronic RTI and others. As subjective and objective side effects, tinnitus and malaise were observed in 5 (4.5%) of 110 patients evaluated for side effects. But, either symptom was mild and disappeared after the end or withdrawal of administration. Slight elevations of S-GPT, BUN and others were observed in 7 cases (6.4%) as abnormal laboratory test values. Safety and efficacy of intravenous drip infusion of ASTM were confirmed.     

Clinical evaluation of astromicin administered by intravenous drip infusion. Report II. Bacterial infections in the field of surgery

A clinical evaluation of astromicin (ASTM) administered by intravenous drip infusion against infections in the surgical field was made, and the results were summarized as follows. Excellent effect was observed in 19 out of a total of 44 cases, good effect in 19, fair in 1 and poor in 5. The efficacy rate calculated from the 38 cases of "excellent" and "good" was 86%. In stratification by disease, the efficacy rate was 91% in localized peritonitis (31/34 cases) and 63% in diffuse peritonitis (5/8 cases); the overall efficacy rate in peritonitis was 86%. The efficacy rate in 2 cases infected by Gram-positive bacteria was 50%, and that in 16 cases by Gram-negative bacteria was 94%. The disappearance rate of Gram-negative bacteria was 93%, and this drug was especially effective against E. coli. There were no subjective or objective side effects and no abnormal laboratory test values that were related to the administration of ASTM.     

Clinical evaluation of astromicin administered by intravenous drip infusion. Report III. Bacterial infections in the field of urology

Intravenous drip infusion of a new aminoglycoside agent, astromicin (ASTM), was used for various urological infections, and its clinical efficacy and safety were studied. Each of almost all the patients tested was given 200 mg of ASTM twice a day by intravenous drip infusion. Among 114 cases with complicated urinary tract infections (UTI) evaluated according to the criteria for evaluation of drug efficacy in UTI, clinical response was excellent in 16, moderate in 54 and poor in 44. The efficacy rate was 61.4%. Among 137 cases who were evaluated for side effects, headache was observed in 1 case (0.7%), which recovered spontaneously the day after the withdrawal of the drug. Slight elevation in S-GOT, S-GPT, Al-P and others was observed in 12 cases (8.8%) as abnormal laboratory test values.     

A phase I study on intravenous drip infusion of astromicin

A phase I study on intravenous drip infusion of astromicin (ASTM, KW-1070), an aminoglycoside antibiotic, was performed on 9 healthy adult male volunteers to investigate the safety and pharmacokinetics of this drug. ASTM 200 mg was dissolved in 250 ml of saline and given to each of 6 volunteers by drip infusion in 1 hour. For comparison, 200 mg of ASTM in 1 ml of saline was injected intramuscularly. No subjective and objective reactions were found, and laboratory test value did not show any change possibly caused by ASTM. In a single administration study, Cmax was 10.8 micrograms/ml by intramuscular injection and 12.0 micrograms/ml by intravenous drip infusion. The areas under the time-serum concentration curve were 35.6 micrograms X hr/ml and 34.9 micrograms X hr/ml, respectively; that is, the serum levels of ASTM after one-hour intravenous drip infusion changed almost identically to those after intramuscular injection. In a multiple administration study, the change in serum levels of ASTM after the ninth administration was approximately the same as that after the first one. This means that no accumulation of ASTM in serum occurred. Recovery rates of ASTM in urine up to 8 hours after a single intramuscular injection and a single intravenous drip infusion were 85.4% and 87.5%, respectively. These results also support the conclusion that there is no accumulation of ASTM in the body by repeated administrations.     

Clinical efficiency in children treated with intravenous drip infusion of peramivir

The clinical effect of peramivir was examined retrospectively in 30 children aged 23 days to 8 years; they had been treated with peramivir at our hospital within 48 hours after the onset of influenza from November 2010 to April 2011. Intravenous dripping of peramivir at a dose of 10 mg/kg was performed only once for 15 to 30 minutes. To examine the clinical effect of peramivir, the time from dosing to defervescence (body temperature <37.5 degrees C) was evaluated. To compare the clinical effects of peramivir and oseltamivir, the time required for the defervescence was evaluated in a similar manner in 30 children aged 7 months to 8 years who had been treated for influenza with oseltamivir at a dose of 4 mg/kg/day. The influenza type was type A (n=25) and type B (n=5) in the peramivir group and type A (n=26) and type B (n=4) in the oseltamivir group. In the peramivir group, 5 (16.7%), 16 (53.3%), and 24 (80.0%) patients achieved defervescence within 6, 12, and 24 hours, respectively. In the oseltamivir group, 3 (10.0%) and 6 (20.0%) patients had defervescence within 12 and 24 hours, respectively. The difference between these groups was statistically significant (p<0.05). An increase in the levels of AST and ALT was observed as an adverse reaction in 1 patient. Thus, peramivir was determined to be effective to influenza in children.     

Clinical studies of cefotaxime, administration in intravenous drip infusion, for infectious diseases in the field of obstetrics and gynecology (author's transl)

Therapeutic efficacy and safety of a new cephalosporin for injection, cefotaxime (CTX) have been examined in gynecological infection cases. CTX has demonstrated in this study excellent therapeutic efficacy in infections with aerobes only, anaerobes only and with mixture of aerobes and anaerobes. No side effect has been observed in our patients who had been administered total dose of 8 approximately 28 g during the period of 4 approximately 7 days.     

Bacteriological, pharmacokinetic and clinical evaluations of ceftriaxone in the pediatric field. Pediatric study group of ceftriaxone

Ceftriaxone (CTRX), a new injectable cephem antibiotic agent, was evaluated bacteriologically and clinically for its efficacy and safety in the pediatric field by a study group organized with pediatricians from all over the country. The following are a summary of the results of the evaluation. Antibacterial effects: The inhibition of growth was attained for over 90% of strains of K. pneumoniae, H. influenzae and Salmonella spp. at the concentration of 0.10 micrograms/ml and of strains of S. pneumoniae and E. coli at the concentration of 2.0 micrograms/ml. The CTRX was proved to have excellent antibacterial effects. Absorption and excretion: Thirty minutes after one shot intravenous administration with 10, 20, 40 and 50 mg/kg of CTRX, its serum levels were 73, 124, 169 and 190 micrograms/ml, respectively, a clear tendency of dose-response relationship being noticed. The serum levels decreased only gradually and stayed as high as 10 to 20 micrograms/ml even after 12 hours. The half-lives of the drug were 5.5, 6.3, 6.0 and 4.7 hours for the 4 different dose levels, respectively. Following the intravenous injection with 10, 20 and 40 mg/kg, the urinary excretion rates were 55, 52 and 54%, respectively. Following the one shot intravenous administration or by the drip infusion for 30 minutes with about 50 mg/kg, CTRX levels in the cerebrospinal fluid ranged from 1 to 20.3 micrograms/ml in case of purulent meningitis (5 to 10 micrograms/ml in most cases). Clinical results: A total of 322 cases was enrolled. The efficacy of CTRX was evaluated in 295 cases out of the 322, excluding drop-outs and the cases which did not meet the protocols. The clinical efficacy rate was 94% of 191 cases where the causative bacteria were identified, CTRX being "excellent" in 108 cases and "effective" in 72. In the remaining 104 cases where the causative bacteria were not identified, the efficacy rate was 92%, CTRX being "excellent" in 42 cases and "effective" in 54. Furthermore, the efficacy rate was 89% of 18 cases infected with more than one kind of bacteria. The drug showed "excellent" or better effectiveness in 88% of 75 cases which had not responded to other antibiotics. Bacteriologically, 174 out of 216 strains (93%) which were judged to be causative bacteria disappeared with the use of CTRX. Eighty-five percent of 53 strains which had not responded to other antibiotics disappeared by the CTRX treatment.(ABSTRACT TRUNCATED AT 400 WORDS)     

Clinical studies of intravenous drip infusion of micronomicin. 1. Pharmacokinetics (Part 2). Intravenous Micronomicin Research Group

Following the previous report on pharmacokinetics of micronomicin (MCR) in healthy volunteers, pharmacokinetic studies were made again in patients with different degree of renal impairment, and a nomogram was obtained. MCR at a dose of 60 mg/time was given by 1-hour drip infusion to 14 inpatients who consented to receive MCR (age: 35 to 84 years, Ccr: 17.96 to 104.35 ml/min). The blood collection was performed in accordance with the schedule made upon the degree of renal impairment, and the serum concentration was determined by HPLC method. The results were analyzed by MULT program using two- or one-compartment open model. The serum concentration (Cmax) just after administration of MCR was 5.8 +/- 0.9 microgram/ml (mean +/- S.D.). The biological half-life was 1.81 to 12.35 hours. Taking the above results into consideration together with the previous ones of healthy males, the following correlation was obtained between the elimination constant (Kel or beta) and Ccr calculated from S-Cr.: Kel or beta = 0.0038 X Ccr - 0.0097. Further, no side effect was observed in these studies. Elimination of MCR from blood was dependent on renal function like other aminoglycosides, and so it was possible to estimate the elimination constant from Ccr. From these results, a nomogram for the optimum dosage regimen of MCR was obtained.     

Clinical studies on aspoxicillin in the pediatric field

Studies on efficacy and safety of aspoxicillin (ASPC) were carried out to 14 cases of pediatric infections, and the following results were obtained. Clinical efficacy of ASPC to 10 respiratory infections, 1 urinary tract infection and 1 otitis media was excellent in 6 cases (50%) and good in 6 cases (50%). The efficacy rate was 100%. Bacteriological effect of ASPC to 6 cases which detected the causative organisms (S. aureus, E. faecalis, H. influenzae and P. mirabilis) was eliminate in 3 cases (50%) and replace in 3 cases (50%). The bacterial eliminated rate was 100%. Side effects of ASPC to 14 administered cases were observed in 2 cases, that were urticaria in 1 case and elevation of GOT in 1 case. From the above results, it was concluded that ASPC was the useful and secure antibiotic drug for treatment of infections in pediatric field.     

Clinical studies on cefmenoxime in the pediatric field

Clinical studies in the field of pediatrics have been carried out with cefmenoxime (CMX), a new cephalosporin antibiotic and the following results were obtained. 1. CMX was administered intravenously by drip infusion in 23 patients with infectious diseases. These diseases consist of 10 pneumonia, 1 bronchitis, 6 upper respiratory tract infections, 2 acute pyelitis, 3 other urinary tract infections and 1 Douglas abscess. CMX was effective in all cases except 1 case of pneumonia with pyothorax. 2. No side effects have been observed in all cases. As for abnormal laboratory findings, 2 cases of eosinophilia, slight elevations of GOT in 3 cases and GPT in 2 cases were seen.     

Clinical studies on ceftazidime in the pediatric field

Ceftazidime ( CAZ ) is a newly developed cephalosporin. Clinical studies on this drug was carried out and the results were as follows. Twenty-nine patients (acute purulent tonsillitis 2, acute bronchitis 1, pneumonia 15, acute purulent lymphadenitis 2, pyoderma 1, skin abscess 2 and urinary tract infection 6) were treated with CAZ in doses of 42-1 mg/kg (mean 59 mg/kg) divided 2-3 times per day for 3-10 days (mean 5.7 days) intravenously. The overall efficacy rate was 96.6%. As to adverse reaction, drug fever was observed in 1 patient. Abnormal laboratory data were noted in 4 cases (elevation of serum GOT, GPT and BUN in 1, elevation of serum GOT and GPT in 1, elevation of BUN in 1 and leukopenia in 1).     

Clinical studies on ceftriaxone in the pediatric field

Clinical studies on ceftriaxone (Ro 13-9904, CTRX) were carried out and the results were as follows: Twelve patients (acute purulent tonsillitis 1, pneumonia 6, urinary tract infection 5) were treated with CTRX, in doses of 21-48 mg/kg divided 2 times per day for 3.5-8 days intravenously. The overall efficacy rate was 100%. No adverse reactions were observed. No abnormal laboratory data were noted.     

Clinical evaluation of ototoxicity associated with intravenous drip infusion of amikacin

On the 53 patients with ENT (ears, nose, and throat) diseases, ototoxicity after intravenous drip infusion of amikacin (Biklin AMK) was studied. Each dose of AMK was 400 mg/day in adults and 4--8 mg/kg/day in children. From audiometric analysis, there were no patients with any hearing disturbances and subjective complaints concerning labyrinth injury. Also abnormal laboratory findings were not found in them. An intravenous drip infusion of AMK in adequate dosage would be beneficial to use against some infectious diseases of otorhinolaryngologic field.     

Studies on tobramycin by the intravenous drip infusion method

Fundamental and clinical efficacy evaluation has been made in the study on the therapy with intravenous drip infusion of tobramycin (TOB) which is one of the aminoglycoside antibiotics and which has been recently approved of intravenous administration. The fundamental evaluations were made with intravenous drip infusion of 60 mg of TOB for 1 hour and that of 120 mg of TOB for 2 hours to 4 healthy adult volunteers on crossover method. Follow-up determinations were made for comparison on its concentrations in blood and urine samples which were collected both at intervals thereafter, using 2 assay methods of the bioassay and the EMIT methods. The maximum blood level of TOB based on the intravenous drip infusion of 60 mg for 1 hour was 5.9 micrograms/ml and 4.6 micrograms/ml by the bioassay and the EMIT methods at the end of intravenous drip infusion, respectively, and 0.3 micrograms/ml and 0.4 micrograms/ml, respectively, at 6 hours after the drip infusion. The T 1/2 value was 1.81 hours with bioassay and 2.41 hours with the EMIT method. The maximum blood level of TOB through drip infusion method of 120 mg of TOB for 2 hours was 7.5 micrograms/ml by bioassay and 5.8 micrograms/ml by EMIT method. The T 1/2 value was 1.87 hours and 1.99 hours, respectively. The recovery rate of TOB from urine until 24 hours after the administration was 83.0% and 94.4% with the doses of 60 mg and 120 mg, respectively, which were determined only with the bioassay. The correlation coefficient between the agar well method and the EMIT method was 0.963 and 0.972 in the groups of intravenous drip infusion of 60 mg for 1 hour and 120 mg for 2 hours, respectively, showing proximity to each other. TOB was kept administered with a daily dose of 120 mg at a time to 11 cases and at 2 times to 1 case with chronic complicated infections of urinary tracts (comprising 9 cases with chronic complicated cystitis, 2 with chronic complicated pyelonephritis, and 1 with acute epididymitis). Of the 12 patients, 8 could meet the criteria for evaluation of drug efficacy and 6 of them proved to be effective, while 2 were ineffective. The efficacy rate was so high as 75%. The rate of disappearance of bacteria was 80.0%, which was very high. No side effect was specifically found out, except 1 case showing slight rise in S-GOT.