Pharmacokinetic and clinical evaluation of cefozopran in premature and newborn patients

Cefozopran (SCE-2787, CZOP), which is already on the market with a variety of approved indications in infectious diseases for adult patients, was administered to premature and newborn patients to evaluate the pharmacokinetics and the clinical efficacy. 1. Pharmacokinetics CZOP was intravenously administered at doses of 10.0 mg/kg, 21.4 mg/kg and 40.0 mg/kg to premature and newborn patients, and the blood concentrations and urinary excretion rate were examined. The blood CZOP concentrations were 31.7 and 65.5 micrograms/ml at 30 minutes after administration of 10.0 mg/kg and 40.0 mg/kg, respectively. The elimination half life was 1.78 hours and 2.31 hours, and the urinary recovery was 110.7% and 53.7% within 6 hours after administration, respectively. In the patient given 21.4 mg/kg, the blood CZOP concentration was 36.4 mg/kg at 1 an hour after administration and the elimination half life was 3.97 hours. The urinary recovery was 29.6% within 5 hours after administration. 2. Clinical results The clinical efficacy was evaluated in 19 patients and judged "good" or better in 13 of them with the efficacy rate or 68.4%. The bacteriological response was evaluated in 10 patients from whom Gram-positive cocci of S. aureus (6 strains), S. pneumoniae (1 strain) and E. faecalis (1 strain) and Gram-negative bacilli of H. influenzae (2 strains) and E. coli (2 strains) were isolated as possible causative organisms. With exception of 1 strain each of S aureus and H influenzae, which were not tested after the treatment with CZOP, all of these strains were found to be eradicated. 3. Adverse drug reactions (ADRs) of signs and symptoms and abnormal alterations of laboratory test values. Safety evaluation was made in 24 patients. ADRs of signs and symptoms were recognized in none of them. As abnormal alterations of laboratory test values, increased eosinophils in 3 patients, elevated GOT in one and elevated GPT in one were recognized. These results indicate that CZOP is a drug useful for treatment of infections in premature and newborn patients.     

Pharmacokinetics and clinical effects of cefozopran in pediatric patients

An investigation was made into pharmacokinetics and clinical effects of the newly-developed cephem antibiotic for injection, cefozopran (SCE-2787, CZOP), in pediatric patients. In 26 patients in whom pharmacokinetics were investigated, peak serum concentrations of CZOP administered at doses of 10, 20 and 40 mg/kg by i.v. injection were 21.3 +/- 10.0 (mean +/- standard deviation), 51.0 +/- 9.9 and 68.3 +/- 0.7 micrograms/ml, respectively. Serum concentrations at 6 hours after administration were 2.9 +/- 1.7, 2.3 +/- 0.9 and 4.6 +/- 2.6 micrograms/ml, with the levels roughly above MIC90s for dominating pathogenic bacteria being maintained until 6 hours after treatment. Urine concentrations were in the range between 200 and 560 micrograms/ml at 4 to 6 hours after dosing. Cumulative urine excretion accounted for 70 to 80% of dose. In 11 patients in whom pharmacokinetic investigations were performed, peak serum concentrations of CZOP administered at doses of 10, 20 and 40 mg/kg by 30-min. i. v. drip infusion were 37.1, 66.3 +/- 25.5 and 95.7 +/- 8.9 micrograms/ml, respectively. Serum concentrations at 6 hours after dosing were 1.6, 2.3 +/- 0.8 and 3.0 +/- 0.4 micrograms/ml, respectively, with the levels above MIC90s for dominating pathogenic bacteria also being maintained until 6 hours after administration. Urine concentrations were 190 micrograms/ml or more until 8 hours after dosing and the cumulative urinary excretion accounted for 50 to 70% of dose. In 9 patients with meningitis in whom CZOP penetration into cerebrospinal fluid was investigated, concentrations in the fluid of the compound i.v. injected at doses from 40 to 53 mg/kg were in the range between 1.6 and 43.4 micrograms/ml exceeding MICs for pathogenic bacteria at 1 to 1.5 hours after dosing. In all of the 38 patients in whom pharmacokinetic investigations and clinical evaluations were performed, CZOP was good to excellent (excellent in 22 patients and good in 16 patients). Also in bacteriological evaluations, all of the 31 strains of investigated pathogenic bacteria were eradicated. The clinical efficacy rates for the 335 subjects for clinical evaluations were 97.0% (195/201) for patients in whom pathogenic bacteria were detected (group A), and 95.5% (128/134) for patients in whom no pathogenic bacteria were detected (group B). In bacteriological evaluations, the eradication rates of Gram-positive and Gram-negative bacteria were 96.3% (77/80) and 94.5% (155/164), respectively, with the eradication rate in total being 95.1% (232/244). Safety investigations were performed in 364 patients. Adverse reactions were reported in 11 patients (3.0%), including diarrhea (aqueous stool and soft stool) in 7 patients (1.9%) and drug rash (rash, eruption and wheal) in 4 patients (1.1%). Abnormal laboratory test values were noted in 54 patients, including eosinophilia in 20 patients (6.3%) and elevated GPT in 20 patients (6.3%). The adverse reactions and abnormal laboratory test values were not serious, disappearing or improving during the continued treatment period or as a result of discontinuation of the treatment. Serum and urine concentrations of CZOP, when administered by i.v. injection and 30-min, i.v. drip infusion at doses of 10, 20 and 40 mg/kg, were higher than the MICs for pathogenic bacteria until 6 hours after dosing. The drug also showed favorable penetration into cerebrospinal fluid. It was therefore considered that CZOP was a highly useful drug for the treatment of pediatric infections with sufficient bacteriological and clinical efficacy when administered at a dose of 40 to 80 mg/kg three to four times daily.     

Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus

This study evaluated the safety, tolerability, and pharmacokinetics of zidovudine administered intravenously and orally to infants born to women infected with the human immunodeficiency virus. Thirty-two symptom-free infants were enrolled before 3 months of age. The pharmacokinetics of zidovudine were evaluated in each infant after single intravenously and orally administered doses of zidovudine on consecutive days, and during long-term oral administration of the drug for 4 to 6 weeks. As new patients were enrolled, doses of zidovudine were progressively increased from 2 to 4 mg/kg. Therapy was continued for up to 12 months in 7 of the infants proved to be infected with human immunodeficiency virus. Zidovudine was generally well tolerated; 20 children (62.5%) had anemia (hemoglobin level < 10.0 gm/dl) during therapy and 9 (28.1%) had neutropenia (neutrophil count < or = 750 cells/mm3); these hematologic abnormalities usually resolved spontaneously. The total body clearance of zidovudine increased significantly with age, from an average of 10.9 ml/min per kilogram in infants < or = 14 days of age to 19.0 ml/min per kilogram in older infants (p < 0.0001). Concurrently, there was a significant decrease in serum half-life from 3.12 hours in infants < or = 14 days to 1.87 hours in older infants (p = 0.0002). Oral absorption was satisfactory and bioavailability decreased significantly with age, from 89% in infants < or = 14 days to 61% in those > 14 days of age (p = 0.0002). Plasma concentrations of zidovudine were calculated to be in excess of 1 mumol/L (0.267 micrograms/ml) for 4.12 +/- 1.86 hours and 2.25 +/- 0.78 hours after oral doses of 2 mg/kg in infants younger than 2 weeks and 3 mg/kg in older infants, respectively. We conclude that zidovudine administered at oral doses of 2 mg/kg every 6 hours to infants aged less than 2 weeks and 3 mg/kg every 6 hours to infants older than 2 weeks resulted in plasma concentrations that are considered virustatic against human immunodeficiency virus. Zidovudine was well tolerated by infants at these doses.     

Phase I safety and pharmacokinetics study of micronized atovaquone in human immunodeficiency virus-infected infants and children. Pediatric AIDS Clinical Trials Group

A phase I dose-escalating safety and pharmacokinetic study evaluated an oral suspension of micronized atovaquone (m-atovaquone) in infants and children stratified into age groups from 1 month to 12 years of age. Dosages of 10, 30, and 45 mg/kg of body weight/day were evaluated as single daily doses over a period of 12 days. Steady-state concentrations in plasma were determined on day 12, and single postdose concentrations were measured on days 1, 3, 5, 7, 9, 13, 15, 18, 21, and 24. Prior studies with adults suggest that the average plasma atovaquone concentration of 15 micrograms/ml is associated with therapeutic success in more than 95% of patients with Pneumocystis carinii pneumonitis. The results showed m-atovaquone to be safe and well tolerated. Dosages of 30 mg/kg/day were adequate to achieve an average steady-state concentration of greater than 15 micrograms/ml in children ages 1 to 3 months and 2 to 12 years, but a dosage of 45 mg/kg/day was needed to reach this concentration in infants 3 to 24 months of age. The oral suspension of atovaquone is safe and well tolerated in children. A single daily dose of 30 mg/kg provides bioavailability considered adequate for therapy of P. carinii pneumonia, but infants between 3 and 24 months of age may require a dosage of 45 mg/kg/day.     

Pharmacokinetic and clinical evaluation of azithromycin in pediatrics

Azithromycin (AZM), a new macrolide antibiotic, in fine granules and in capsules was administered at a standard dose of 10 mg/kg once daily for 3 days to pediatric patients with bacterial infections. AZM was studied for its pharmacokinetic and clinical evaluation. 1. AZM possessed potent activity against Gram-positive bacteria and Gram-negative bacteria that had been clinically isolated. 2. Plasma samples were collected from two patients diagnosed as having pneumonia or enteritis, and urine samples were collected from one patient diagnosed as having pneumonia for drug level determination. The drug concentrations in plasma were 0.095 and 0.204 microgram/ml just before the end of treatment, and 0.017 and 0.096 microgram/ml at 48 hours post-treatment. The drug concentrations in urine were 5.16 micrograms/ml and 5.63 micrograms/ml during a period between 24 and 48 hours and between 48 and 72 hours after the start of treatment, respectively. 3. The drug was found effective in 37 of 38 cases with various pediatric infections. AZM treatment eradicated bacteria in 17 of 30 strains (56.7%). 4. One patient complained of mild vomiting, while abnormal laboratory test results indicating mild eosinophilia were reported in four cases.     

Phase I study of intraventricular recombinant tissue plasminogen activator for treatment of posthaemorrhagic hydrocephalus

AIM: Phase I study to evaluate intraventricular fibrinolytic treatment with recombinant tissue plasminogen activator (tPA) as a method of clearing blood from the cerebrospinal fluid, and thus preventing permanent hydrocephalus. METHODS: Twenty two preterm infants, aged 7 to 26 days, with progressive posthaemorrhagic ventricular dilatation (ventricular width > 4 mm over 97th centile) received one to five intraventricular bolus injections of 1.0 mg or 0.5 mg tPA at intervals of one to seven days. RESULTS: The mean cerebrospinal fluid concentration of tPA 24 hours after 1 mg was 1860 micrograms/ml. The half life of tPA in cerebrospinal fluid was about 24 hours. Twenty one (95%) infants survived, 12 (55%) without shunt surgery. One infant had secondary intraventricular haemorrhage. CONCLUSION: Intraventricular tPA resulted in survival without a shunt for most of the infants, but with some risk. Failure may have been due to plasminogen deficiency, an inhibitor, or late intervention.     

Clinical study on azithromycin in 10% fine granules and 100mg capsules in the field of pediatrics

Azithromycin (AZM), a new oral macrolide antibiotic, in 10% fine granules or 100 mg capsules was given to pediatric patients to treat various infections. The following results were obtained in our studies of AZM for its antibacterial activities against clinical isolates, its pharmacokinetics, its efficacy, and its safety. 1. MICs of AZM, erythromycin (EM) and clarithromycin (CAM) were determined against a total of 57 strains all at 10(6) cfu/ml. Among Gram-positive cocci, MICs of AZM ranged from 0.78 to > 100 micrograms/ml against Staphylococcus aureus (20 strains), from 0.05 to 0.1 microgram/ml against Streptococcus pyogenes (11 strains), and from 0.0125 to 3.13 micrograms/ml against Streptococcus pneumoniae (10 strains). These MICs were similar to those of the other macrolides. Among Gram-negative bacilli, MICs of AZM were 0.05 micrograms/ml against Moraxella subgenus Branhamella catarrhalis (1 strain), from 0.78 to 3.13 micrograms/ml against Haemophilus influenzae (9 strains), 0.78 micrograms/ml against Haemophilus parainfluenzae (1 strain) and 6.25 micrograms/ml against salmonella sp. (1 strain). These values were similar to or lower than those of the other macrolides. Against Mycoplasma pneumoniae, MICs of AZM were < or = 0.0008 micrograms/ml in three strains. One strain of M. pneumoniae showed tolerance to AZM at MIC 25 micrograms/ml. The other agents exhibited higher MIC than AZM against this organism. 2. Plasma samples were collected from five patients receiving fine granules and four patients receiving capsules for drug level determination. The patients received AZM at 10.0 approximately 16.3 mg/kg body weight once daily for 3 days. Drug concentrations in plasma at two hours after Day 3 dosing were in a range between 0.02 and 0.19 micrograms/ml for fine granules and were in a range between 0.11 and 0.42 micrograms/ml for capsules. 3. Urine samples were collected from four patients receiving fine granules and four patients receiving capsules. Drug levels were determined to be 3 micrograms/ml at post-treatment 48 hours for fine granules and post-treatment 72 hours for capsules. Urinary excretion rates of AZM in three patients on capsules lied in a range between 4.69 and 10.17%. 4. Effectiveness of AZM in fine granules was evaluated in 128 patients having a total of 19 different infections. AZM was rated "excellent" in 51 patients, "good" in 63, "fair" in 8, "poor" in 6, resulting in an efficacy rate of 89.1%. Effectiveness of AZM in capsular form was evaluated in 23 patients with five different infections. AZM was found "excellent" in 13 patients and "good" in 10, resulting in an efficacy rate of 100%. 5. AZM in fine granules eradicated 45 strains of 54 in 8 different bacteria. AZM in capsules eradicated 9 strains of 10 strains in 6 different bacteria. 6. As for adverse reactions, one patient complained of eruption, one vomiting, one loose stool, five diarrhea, when administered with fine granular form of AZM. One patient on AZM capsules experienced urticaria and vomiting. 7. As for abnormal laboratory changes, three patients were found with decreased WBC, seven with increased eosinophil, two with increased GOT and GPT, one with increased GPT. They were all on fine granular form of AZM. As far as abnormalities found in patients administered with AZM in capsular form, two showed decreased WBC, one decreased WBC along with increased eosinophil, and three increased eosinophil.     

Bacteriological, pharmacokinetic and clinical evaluation of azithromycin in the pediatric field]

Azithromycin (AZM), a new macrolide antibiotic, in fine granules and in capsules was studied for pharmacokinetic and clinical evaluation in the pediatric patients. Antibacterial activity of AZM against 43 clinical isolates: AZM exhibited slightly lower activity against Gram-positive bacteria and 2-8-fold higher activity against Gram-negative bacteria than erythromycin or clarithromycin. Plasma or urine samples were collected from eight patients receiving the drug in fine granular form, and two patients receiving it in capsules for the determination of drug levels. The elimination half-lives of AZM after administration at dose of 10 mg/kg/day for 3 days were 50.0 and 51.2 hours for fine granules, and 41.5 hours for capsules. AUC0-infinity was 11.7 and 24.3 micrograms.hr/ml for fine granules, and 8.3 micrograms.hr/ml for capsules. The cumulative excretion rates up to 120 hours after the start of treatment were 8.24 and 13.84% for fine granules, and 3.83% for capsules. AZM was administered to 123 patients once daily at 3.7-20.0 mg/kg body weight over 3 to 5 days with reference to the standard dose of 10 mg/kg. The drug was used to treat patients with pharyngitis, tonsillitis, scarlet fever, pneumonia, mycoplasmal pneumonia, chlamydial pneumonia, otitis media, pertussis, intestinal infection, and SSTI. The effectiveness of AZM was evaluated in 109 cases. The drug was rated "excellent" in 65.1% of the patients and "good" in 29.4%, resulting in an efficacy rate of 94.5%. Furthermore, AZM eradicated 43 of 46 (93.5%) bacteria that had been identified before the treatment. Three patients complained of side effects of urticaria (1 case) and diarrhea (2 cases). Abnormal laboratory changes were reported as follows: decreased leukocyte (3 cases), increased eosinophil (5), increased platelet (2), increased eosinophil and platelet, elevated GPT (1), and elevated GOT and GPT (1). The abnormalities, however, were mild enough to raise no clinically significant problems. In conclusion, AZM in once daily regimen was effective and safe in treatment of pediatric infections.     

Reinfusion of whole blood following addition of tobramycin powder to the wound during total knee arthroplasty

This study prospectively examined nine human volunteers who underwent unilateral cementless total knee arthroplasty and had 600 mg of tobramycin powder added to their wound just prior to fascial closure. Serum levels of tobramycin were measured at 30 minutes, 4 hours, 8 hours, and 12 hours after surgery. Tobramycin levels in the reinfused whole blood were measured with each reinfusion. Patients were reinfused up to 12 hours after surgery and then the reservoir was left to suction drainage. All patients had significant levels of serum tobramycin 30 minutes after surgery. The average serum level was 5.5 micrograms/ml (range, 3.0-10.6 micrograms/ml). This level was achieved prior to any reinfusion and represented systemic absorption of tobramycin from the bleeding surfaces of the muscle and bone. All patients received at least one reinfusion of 400 ml of whole blood in the first 8 hours after surgery. Two thirds of the patients received a second reinfusion within the same time frame. Serum tobramycin levels measured post-reinfusion indicated that the risk of attaining potential toxic levels of aminoglycoside was not dependent on reinfusion, but on absorption from the wound. The dose of tobramycin in the drain was measured and found to be excessive and potentially toxic (range, 27-312 mg; average, 132 mg). Despite this fact, reinfusion was not as likely to produce toxic serum levels as was local uptake of the antibiotic. Although no patient in this series had any complaints relating to the high dose of tobramycin (deafness or renal failure), caution should be exercised when using antibiotics in a reinfusion system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic and clinical studies on biapenem (L-627) in the pediatric field

Pharmacokinetic and clinical studies on biapenem (L-627), a newly developed carbapenem, were performed and the following results were obtained. 1. Absorption/excretion: Pharmacokinetics of biapenem was studied in 14 children at doses of 6 mg/kg and 12 mg/kg administered through 30 minutes-drip infusion. Peak plasma levels and plasma half-lives of the 2 doses were 22.5, 29.9 micrograms/ml, and 0.84, 0.85 hours, respectively. Their urinary recovery rates were 54.5 to 76.1% and 37.3 to 59.5%, respectively. Cerebrospinal fluid levels of biapenem in two patients with purulent meningitis were 0.88 and 2.72 micrograms/ml, and the penetration rates were 3.7 to 8.3%. 2. Clinical study: Forty-nine patients were treated with biapenem at doses exceeding 90 to 100 mg/kg/day for purulent meningitis and at doses between 15.0 and 36.0 mg/kg/day for other infections. Biapenem gave "Excellent" or "Good" responses in 48 cases, hence an efficacy rate of 98.0% was obtained. Only one patient with pneumonia showed a fair response. No adverse reactions were observed. Abnormal laboratory test results were noted in 7 patients including elevation of GOT, GPT, and eosinophils. In no cases the treatment had to be discontinued.     

Calcium-dependent chloride current activated by hyposmotic stress in rat lacrimal acinar cells

Pharmacokinetic and clinical studies on DQ-2556, a new cephem antibiotic, in obstetrics and gynecology were performed and following results were obtained. Concentrations of DQ-2556 were determined in serum, internal genital organs and retroperitoneal exudate after single intravenous administration (i.v.) or drip infusion (d.i.v.) of 1.0 g. Serum levels following i.v. were approximately 30 micrograms/ml at 1 hour, 14 micrograms/ml at 3 hours 30 minutes, and concentrations in internal genital organs including oviduct, ovary, endometrium, myometrium, cervix uteri and portio vaginalis reached approximately 50% to 70% levels of serum concentration. The mean concentration (n = 6) in the retroperitoneal exudate after d.i.v. of 1.0 g following radical hysterectomy were about 20 micrograms/ml, 23 micrograms/ml, 14 micrograms/ml and 8 micrograms/ml at 1 hour, 2 hours 30 minutes, 4 hours 30 minutes and 6 hours 30 minutes, respectively. In clinical trials, DQ-2556 (2.0 g b.i.d. for daily dose) was given in 5 patients with gynecological infections such as pyometra (1 case), salpingitis (1), retroperitoneal space infection (2), pelvic peritonitis (1). The clinical results were evaluated as good in 3 cases and poor in 2 cases including a case with salpingitis infected by Pseudomonas aeruginosa and the other with pelvic peritonitis caused by Methicillin-resistant Staphylococcus aureus. Bacteriologically, 11 organisms were isolated from patients, and eradication rate was 54.5%. Neither side effect nor abnormal laboratory test result was observed. Thus, DQ-2556 appears to be effective for gynecological infections, and the good results were supported by good penetration of the compound into tissues of internal genital organs and retroperitoneal exudate after i.v. or d.i.v.     

In vitro and in vivo antibiotic susceptibility of Lyme disease Borrelia isolated from the ixodid tick in Japan

Antimicrobial susceptibility of the Lyme disease Borrelia, strain HP1 vi, isolated from the tick ixodes persulcatus in Hokkaido, Japan, was determined in vitro and in vivo. A broth dilution technique was used to determine the minimum inhibitory concentrations (MICs) and minimum borreliacidal concentrations (MBCs) of five antimicrobial agents. Strain HP1 vi was most susceptible to minocycline (MBC, 0.2 micrograms/ml). The other antimicrobial agents tested, aspoxicillin, cefmetazole sodium, imipenem cilastatin sodium, and panipenem betamipron, had higher MBCs of 12.5 micrograms/ml, 25 micrograms/ml, > 25 micrograms/ml, and > 25 micrograms/ml, respectively. In vivo antibiotic susceptibility study using a ddY mouse model demonstrated that minocycline and amoxicillin were effective; minocycline had a lower 50% effective dose (ED50) value (6.25 mg/kg) than amoxicillin (30 mg/kg).     

Pharmacokinetic properties of gentamicin and amikacin in the cockatiel

Gentamicin and amikacin are commonly used in veterinary medicine to treat a variety of gram-negative bacterial infections. The present study evaluates the pharmacokinetics of gentamicin sulfate and amikacin sulfate in the cockatiel (Nymphicus hollandicus), a small (approximate body weight = 100 g) psittacine bird, utilizing treatment regimens developed in larger parrot species. Serum antibiotic concentrations were determined in cockatiels following twice-daily intramuscular treatment with 5 mg gentamicin/kg body weight and 15 mg amikacin/kg body weight. In the present study, peak values of gentamicin were 4.6 +/- 1.45 micrograms/ml, and trough values were 0.17 +/- 0.04 micrograms/ml. Amikacin administration resulted in peak values of 27.3 +/- 6.9 micrograms/ml and trough concentrations of 0.9 +/- 0.3 micrograms/ml. Based on the present study, an appropriate intramuscular dose regimen for gentamicin in cockatiels is 5 to 10 mg/kg body weight either two or three times per day. An intramuscular amikacin dosage of 15 to 20 mg/kg body weight either two or three times per day is recommended for treatment of infections caused by susceptible bacteria.     

Laboratory and clinical studies on tazobactam/piperacillin in the field of pediatrics

Laboratory and clinical studies on tazobactam/piperacillin (TAZ/PIPC), a combination drug of piperacillin (PIPC) with the new beta-lactamase inhibitor tazobactam (TAZ), were carried out in the field of pediatrics. 1. After intravenous administration of TAZ/PIPC at a dose of 25 mg/kg to one child, the peak plasma levels of TAZ and PIPC were 24.4 micrograms/ml and 119 micrograms/ml respectively after 5 min. The half-lives of TAZ and PIPC were 0.48 and 0.60 hours respectively. Same as 50 mg/kg to two children, the peak plasma levels of TAZ and PIPC were 17.5, 32.2 micrograms/ml and 92.8, 163 micrograms/ml after 5 min. The half-lives of TAZ and PIPC were 0.37, 0.50 hours and 0.51, 0.59 hours. A ratio of TAZ to PIPC was about 1 to 4 in plasma levels. The cumulative urinary recovery rates of TAZ and PIPC in the first 6 hours after intravenous administration were 15.8, 64.9% and 39.8, 53.4%. 2. The antibacterial activity of TAZ/PIPC against clinically isolated organisms was determined. The MICs of TAZ/PIPC were < or = 0.05 microgram/ml against Haemophilus influenzae and Streptococcus pneumoniae and > or = 1.56 micrograms/ml against Escherichia coli, Staphylococcus aureus and Haemophilus parainfluenzae. 3. The clinical efficacy of TAZ/PIPC could be evaluated in 14 patients with various bacterial infections, and was evaluated as "excellent" in 9 patients and as "good" in 5. The overall clinical efficacy rate in 14 cases was 100% and excellent was 64.3%. Bacteriological efficacy rate was 91.7% (10/11). 4. As a side effect, loose stool was observed in one case, no abnormal laboratory test values were observed. It has been concluded that TAZ/PIPC was a useful drug in the field of pediatrics.     

Comparative studies on activities of antimicrobial agents against causative organisms isolated from patients with urinary tract infections (1996). I. Susceptibility distribution

The frequencies of isolation and susceptibilities to antimicrobial agents were investigated on 680 bacterial strains isolated from patients with urinary tract infections (UTIs) in 10 hospitals during the period of June 1996 to May 1997. Of the above bacterial isolates, Gram-positive bacteria accounted for 30.4% and a majority of them were Enterococcus faecalis. Gram-negative bacteria accounted for 69.6% and most of them were Escherichia coli. Susceptabilities of several isolated bacteria to antimicrobial agents were as followed; 1. Enterococcus faecalis Ampicillin (ABPC) showed the highest activity against E. faecalis isolated from patients with UTIs. Its MIC90 was 1 microgram/ml. Imipenem (IPM) and vancomycin (VCM) were also active with the MIC90S of 2 micrograms/ml. The others had low activities with the MIC90S of 16 micrograms/ml or above. 2. Staphylococcus aureus including MRSA Arbekacin (ABK) and VCM showed the highest activities against both S. aureus and MRSA isolated from patients with UTIs. The MIC90S of them were 1 or 2 micrograms/ml. The others except minocycline (MINO) had low activities with the MIC90S of 32 micrograms/ml or above. 3. Staphylococcus epidermidis ABK and VCM showed the strongest activities against S. epidermis isolated from patients with UTIs. The MICs for all strains were equal to or lower than 2 micrograms/ml. Cefazolin (CEZ), cefotiam (CTM) and cefozopran (CZOP) were also active with the MIC90S of 4 micrograms/ml. Compared with antimicrobial activities of cephems is 1995, the MIC90S of them had changed into a better state. They ranged from 4 micrograms/ml 16 micrograms/ml in 1996. 4. Streptococcus agalactiae All drugs except MINO were active against S. agalactiae. ABPC, CZOP, IPM, and clarithromycin (CAM) showed the highest activities. The MICs for all strains were equal to or lower than 0.125 micromilligrams. Tosufloxacin (TFLX) and VCM were also active with the MIC90S of 0.5 micromilligrams. 5. Citrobacter freundii Gentamicin (GM) showed the highest activity against C. freundii isolated from patients with UTIs. Its MIC90 was 0.5 micrograms/ml. IPM and amikacin (AMK) were also active with the MIC90S of 1 microgram/ml and 2 micrograms/ml, respectively. Cefpirome (CPR) and CZOP were also active with the MIC90S of 8 micrograms/ml. The MIC90S of the others were 16 micrograms/ml or above. 6. Enterobacter cloacae IPM showed the highest activity against E. cloacae. The MICs for all strains were equal to or lower than 0.5 microgram/ml. The MIC90S of ciprofloxacin (CPFX) and TFLX were 1 microgram/ml, the MIC90 of AMK was 2 micrograms/ml, the MIC90S of CZOP, GM and ofloxacin (OFLX) were 4 micrograms/ml. The MIC50S of cephems except CEZ, cefmetazole (CMZ) and cefaclor (CCL) had changed into a better state in 1996, compared with those in 1995. 7. Escherichia coli All drugs except penicillins and MINO were active against E. coli. Particularly CPR, CZOP and IPM showed the highest activities against E. coli. The MIC90S of them were 0.125 microgram/ml or below. Among E. coli strains, those with low susceptibilities to cephems except CEZ, cefoperazone (CPZ), latamoxef (LMOX) and CCL have increased in 1996, compared with those in 1995. 8. Klebsiella pneumoniae K. pneumoniae was susceptible to all drugs except penicillins, with the MIC90S of 2 micrograms/ml or below. CPR had the strongest activity, the MICs for all strains were equal to or lower than 0.25 microgram/ml. Flomoxef (FMOX), cefixime (CFIX), CZOP and carumonam (CRMN) were also active with the MIC90S of 0.125 microgram/ml or below. 9. Pseudomonas aeruginosa All drugs except quinolones were not so active against P. aeruginosa with the MIC90S were 32 micrograms/ml or above. Quinolones were more active in 1996 than 1995. The MIC90S of them were between 4 micrograms/ml and 8 micrograms/ml, and the MIC50S of them were between 1 microgram/ml and 2 micrograms/ml. 10. Serratia marcescens GM showed the highest activity against S. marcescens. Its MIC90 was 1 micro     

Pulmonary function changes after nebulised and intravenous frusemide in ventilated premature infants

AIMS: To compare the effects of a single dose of frusemide administered either intravenously or by nebulisation on pulmonary mechanics in premature infants with evolving chronic lung disease. METHODS: The effect of frusemide on pulmonary mechanics was studied at a median postnatal age of 23 (range 14-52) days in 19 premature infants at 24 to 30 weeks gestational age, who had been dependent on mechanical ventilation since birth. Frusemide (1 mg/kg/body weight) was administered, in random order, intravenously and by nebulisation, on two separate occasions 24 hours apart. Pulmonary function studies were performed before and at 30, 60, and 120 minutes after administration of frusemide. Urine was collected for six hours immediately before and for six hours after administration of frusemide. RESULTS: Nebulised frusemide increased the tidal volume 31 (SE 11.5)% and compliance 34 (SE 12)% after two hours, whereas no change in either was noted for up to two hours after intravenous frusemide administration. Neither intravenous nor nebulised frusemide had any effect on airway resistance. Six hour urine output increased from a mean (SE) of 3.3 (0.4) ml/kg/hour to 5.9 (0.8) ml/kg/hour following intravenous frusemide administration while nebulised frusemide had no effect on urine output. Urinary sodium, potassium, and chloride losses were also significantly higher after intravenous frusemide, whereas nebulised frusemide did not increase urinary electrolyte losses. CONCLUSION: Single dose nebulised frusemide improves pulmonary function in premature infants with evolving chronic lung disease without adverse effects on fluid and electrolyte balance.     

Comparative studies on activities of antimicrobial agents against causative organisms isolated from urinary tract infections (1993). I. Susceptibility distribution

The frequencies of isolation and susceptibilities to antimicrobial agents were investigated on 657 bacterial strains isolated from patients with urinary tract infections in 10 hospitals during the period of June 1993 to May 1994. Of the above total bacterial isolates, Gram-positive bacteria accounted for 28.3% and a majority of them were Enterococcus faecalis. Gram-negative bacteria accounted for 71.7% and most of them were Escherichia coli. 1. Enterococcus faecalis Ampicillin (ABPC), imipenem (IPM) and vancomycin (VCM) showed the highest activities against E. faecalis isolated from patients with urinary tract infections. The MIC90s of them were 2 micrograms/ml. Piperacillin (PIPC) was also active with the MIC90 of 8 micrograms/ml. The others were not so active with the MIC90s of 32 micrograms/ml or above. 2. Staphylococcus aureus including MRSA VCM showed the highest activities against S. aureus isolated from patients with urinary tract infections. Its MIC90 was 1 microgram/ml. Arbekacin (ABK) was also active with the MIC90 of 2 micrograms/ml. The others were not so active with the MIC90s of 32 micrograms/ml or above. 3. Staphylococcus epidermidis VCM showed the strongest activity against S. epidermidis isolated from patients with urinary tract infections. Its MIC90 was 1 microgram/ml. ABK was also active with the MIC90 of 4 micrograms/ml. The others except ABPC were not so active with the MIC90s of 32 micrograms/ml or above. 4. Streptococcus agalactiae Most of the agents were active against S. agalactiae isolated from patients with urinary tract infections. Penicillins, cephems, erythromycin (EM), and clindamycin (CLDM) showed the highest activities. The MIC90s of them were 0.25 microgram/ml or below. Amikacin (AMK) and minocycline (MINO) showed somewhat low activities with the MIC90s of 16 micrograms/ml. 5. Citrobacter freundii IPM showed the highest activities against C. freundii isolated from patients with urinary tract infections. Its MIC90 was 2 micrograms/ml. Cefozopran (CZOP) and gentamicin (GM) were also active with the MIC90s of 8 micrograms/ml. Penicillins and cephems generally were not so active. 6. Enterobacter cloacae IPM and GM showed the highest activities against E. cloacae. The MIC90s of them were 1 microgram/ml. CZOP and tosufloxacin (TFLX) were also active with the MIC90s of 8 micrograms/ml. Penicillins and cephems except CZOP showed lower activities with the MIC90s of 64 micrograms/ml or above. 7. Escherichia coli Most of antimicrobial agents were active against E. coli. Flomoxef (FMOX), CZOP, IPM, CPFX and TFLX showed the highest activities against E. coli. The MIC90s of them were 0.125 microgram/ml or below. Cefmenoxime (CMX), ceftazidime (CAZ), cefuzonam (CZON), latamoxef (LMOX), carumonam (CRMN), norfloxacin (NFLX) and ofloxacin (OFLX) were also active with the MIC90s of 0.25 microgram/ml. Penicillins and MINO were not so active with the MIC90s of 32 micrograms/ml or above. 8. Klebsiella pneumoniae CZOP, IPM and CRMN showed the highest activities against K. pneumoniae. The MIC90s of them were 0.125 microgram/ml or below. CAZ, CZON, CFIX, CPFX and TFLX were also active the MIC90s of 0.25 microgram/ml. Penicillins were not so active with the MIC90s of 128 micrograms/ml or above. 9. Proteus mirabilis P. mirabilis was susceptible to a majority of drugs. CMX, CAZ, CZON, LMOX, CFIX, CRMN and CPFX showed the highest activities against P. mirabilis isolated from patients with urinary tract infections. The MIC90s of them were 0.125 microgram/ml or below. MINO was not so active with the MIC90 of 256 micrograms/ml or above. 10. Pseudomonas aeruginosa Most of the agents were not so active against P. aeruginosa. IPM showed MIC90 of 8 micrograms/ml.     

Pharmacokinetic and clinical evaluation of tazobactam/piperacillin in the pediatric field

Pharmacokinetic and clinical evaluation was conducted on the combination drug, tazobactam/piperacillin (TAZ/PIPC, YP-14), of newly developed beta-lactamase inhibitor, tazobactam (TAZ), and antibiotic agent of penicillin group for injections, piperacillin (PIPC), and the following results were obtained. 1. Absorption and excretion Both serum levels of TAZ and PIPC after the intravenous drip infusion for 30 minutes at the dose of 25 mg/kg or 50 mg/kg of TAZ/PIPC showed peaks at the end of the intravenous drip infusion (in 30 minutes after the commencement of the administration) with the levels of 11.93 or 26.05 micrograms/ml for TAZ and 49.80 or 107.50 micrograms/ml for PIPC. The halflife times were 0.51 or 0.67 hours for TAZ and 0.51 or 0.54 hours for PIPC. The serum level of desethyl-piperacillin (DEt-PIPC), an active metabolite of PIPC, showed a peak one hour after the end of the intravenous drip infusion (in 90 minutes after the commencement of the administration) with the level of 0.79 or 1.47 micrograms/ml. On the other hand, cumulative recovery ratios into urine were 41.3% or 40.4% for TAZ and 38.7% or 37.8% for PIPC. The recovery ratio for DEt-PIPC, an active metabolite of PIPC, was 1.9% or 0.3%. 2. Clinical evaluation TAZ/PIPC was administered to 47 cases (pneumonia: 25 cases, bronchitis: 16 cases, cutaneous soft tissue infection: 3 cases, urinary tract infection: 2 cases and lymphadenitis: 1 case). Clinical efficacy evaluation was conducted in 45 cases, excluding one case with bronchitis complicated by measles and other one case with left cervical cellulitis complicated by mumps. Good or more efficacy was observed in the all cases (excellent efficacy: 28 cases and good efficacy: 17 cases). The eradication rate in 31 cases where the pathogenic bacteria were identified and bacteriological efficacy was revealed was 93.5% (29/31 cases). Out of them, bacterial replacement was observed in 5 cases. Decrease in bacteria (including partial eradication) was observed in the remaining 2 cases. Adverse reactions were not reported in any cases. Abnormal values of clinical laboratory examination were reported in 5 cases (increase in platelet count: 2 cases, decrease in leukocyte count: 2 cases and increase in eosinophil count: 1 case). However, there was no case requiring any treatment.     

Comparative intraocular penetration of topical and injected cefuroxime

AIMS: The choice of a prophylactic antibiotic for cataract surgery is dependent on its antibacterial activity and tissue penetration. The influence of the route and timing of administration of cefuroxime on its intraocular concentrations was examined. METHODS: 120 patients were recruited before cataract surgery into a prospective trial to compare the anterior chamber concentration of cefuroxime at a fixed time after administration by three routes. In a further 110 patients, the interval before sampling was varied in order to permit an examination of the kinetics of penetration. In another 10 patients, cefuroxime was given topically at the completion of surgery to assess the effect of a corneal wound on aqueous penetration. Cefuroxime concentrations were measured by high performance liquid chromatography on 0.2 ml samples of aqueous aspirated from the anterior chamber. Mean aqueous concentrations of cefuroxime for each group were compared using Student's t test. RESULTS: After 25 mg cefuroxime, mean aqueous concentrations increased in the order forniceal (< 0.1 microgram/ml) < topical (0.18 microgram/ml) < subconjunctival (2.31 microgram/ml) when sampled 12-24 minutes after administration. Aqueous concentrations of cefuroxime reached a peak between 80 and 110 minutes after both forniceal and peribulbar injection but were still rising at this time after subconjunctival injection. Topical application of 12.5 mg cefuroxime to eyes with a 10 mm corneal wound resulted in a mean aqueous concentration of 9.34 micrograms/ml. CONCLUSION: In the intact eye, only sub-conjunctival injection resulted in clinically significant aqueous concentrations of cefuroxime (> 1 microgram/ml) between 12 and 24 minutes after administration. For all routes, maximal aqueous concentrations were delayed by at least 80 minutes from administration. In the presence of a corneal wound, high aqueous levels of cefuroxime were rapidly attained after topical application.     

Pharmacokinetic, bacteriological and clinical evaluation of tazobactam/piperacillin in pediatrics

Pharmacokinetic, bacteriological and clinical studies were performed in pediatrics on tazobactam/piperacillin (TAZ/PIPC), a combined drug of a new beta-lactamase inhibitor tazobactam and piperacillin at a ratio of 1:4. 1. Serum levels and urinary excretions of TAZ, PIPC and desethyl piperacillin (DEt-PIPC), a metabolite of PIPC, after one shot intravenous administration of 50 mg/kg of TAZ/PIPC to two children (6-7 years old) were investigated. The serum TAZ level at 0.08 hour was 50.8-51.0 micrograms/ml after administration. Then TAZ concentrations gradually decreased with half-lives of 0.38-0.45 hour, and reached 1.0-1.4 micrograms/ml after 2 hours and was not detected after 3 hours and 6 hours. Serum PIPC levels at 0.08 hour was 167.0-231.0 micrograms/ml after administration. Then PIPC concentrations gradually decreased with half-lives of 0.41-0.55 hour, and reached 1.2-2.4 micrograms/ml after 3 hours and was not detected after 6 hours. DEt-PIPC was detected slightly in serum. A ratio of TAZ to PIPC was about 1 to 4 in serum at each time. Urinary recovery rates of TAZ in the first 6 hours after administration of TAZ/PIPC were 33.5-90.1% and those of PIPC were 41.9-77.8% and those of DEt-PIPC were 1.5-2.8%. 2. TAZ/PIPC was administered to 27 pediatric patients (their ages ranged between 2 months and 11 years old) with various infections, and clinical and bacteriological effects and adverse reactions were investigated. Single doses were 26.2-55.6 mg/kg, frequencies of administration were 3-4 times a day, and durations of administration were 3 1/3-7 1/3 days, and total dosages were 4.5-33.75 g. Clinical effects were evaluable in 26 cases. Responses were rated as "good" in acute purulent tonsillitis 1 case and acute purulent otitis media 1 case, as "excellent" in acute sinusitis 1 case, as "excellent" in 2 and "good" in 1 out of 3 cases of acute bronchitis, as "excellent" in 13 and "good" 2 out of 15 cases of acute pneumonia, as "excellent" in acute urinary tract infection 2 cases and as "excellent" in acute enteritis in 1 case, acute appendicitis in 1 case and lymphadentis in 1 case. In all cases, the results were rated as "good" or "excellent". Antimicrobial effects against a total of 10 strains identified or assumed to be pathogenic bacteria were evaluated. The 10 strains of bacteria included 4 strains of Streptococcus pneumoniae, 3 strains of Haemophilus influenzae (2 strains beta-lactamase producing), 2 strains of beta-lactamase producing Moraxella catarrhalis, 1 strain of beta-lactamase producing Morganella morganii. All the bacteria listed here were judged to have been eradicated. Adverse reaction was observed in 1 case with mild diarrhea. As abnormal changes in laboratory data, leucocytopenia in 1 case, elevation of GOT. GPT in 2 cases and eosinophilia in 1 case were observed. On the basis of the findings, TAZ/PIPC was considered to be effective and safe in the treatment of pediatric infections.