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1. The metabolism and pharmacokinetics of 14C-meropenem were studied in five volunteers who received 0.5 g (40 microCi) of the radiolabelled drug by i.v. infusion. 2. The maximum concentration of drug in plasma was 27 +/- 2 micrograms/ml (70 microM) corresponding to 98% of plasma radioactivity at the end of a 30 min infusion. The elimination half-life for meropenem in plasma was 1 h and meropenem remained the major radioactive component up to 6 h, but represented a decreasing proportion of the plasma radioactivity with time. One metabolite (the ring-open lactam) accounted for most of the remaining plasma radioactivity. The maximum concentration of metabolite was 1 +/- 0.1 micrograms/ml and the concentration of total radioactivity decreased to 2% of the peak value by 8 h. 3. Over the 5 days of the study, urinary excretion of radioactivity accounted for 99 +/- 0.5% dose, most of which was recovered in the first 8 h. There was negligible excretion in faeces. 4. Structural confirmation of the drug-related components in urine was accomplished by h.p.l.c.-mass spectrometry. Meropenem accounted for 71 +/- 2% dose of 14C and the ring-open lactam metabolite for most of the remainder, no other metabolites were detected. 5. Meropenem was the major radioactive component in urine up to 8 h after dosing and is therefore remarkably stable to human renal dehydropeptidase (DHP-1) compared with other carbapenems in clinical use.

The pharmacokinetics of meropenem were investigated to examine its penetration into the skin of third degree burned rats. The rats were divided into two groups. One group acted as the control, and the other group had third degree burns induced by immersing their backs into 80 degrees C water for 20 seconds. The rats in each group were given 20 mg/kg of body weight of meropenem intravenously by one bolus injection seven days after burn inducement or depilation. In the non-burned control group, the maximum concentrations of meropenem in the serum and skin of 6.03 micrograms/ml and 0.12 microgram/g were respectively obtained 15 minutes after the injection and decreased very rapidly thereafter. In the burned rats, the maximum concentrations of meropenem in the serum, skin (eschar), and exudate fluid of 7.07 micrograms/ml, 1.44 micrograms/g and 5.99 micrograms/ml were respectively obtained 15 minutes after the injection and decreased very slowly. The penetration of meropenem into the burned skin was higher than that into the normal skin. These results suggest that meropenem is a very useful antibiotic in the treatment of burn infection.

A solution of 0.5 g of meropenem (MEPM) in 100 ml of saline was administered to adult patients before the orthopaedic surgery via intravenous drip infusion for 30 minutes. Eleven samples of bone marrow blood, 13 bone, 8 joint fluid and 8 joint tissues obtained from 15 clinical cases were analyzed for MEPM levels. At the same time, blood samples were taken from peripheral veins and serum served as control was analyzed. The concentration of MEPM in the marrow blood at 30 minutes after administration of MEPM reached 15.4 micrograms/ml, which was above 50% of the maximum concentration in serum. Ratios of concentration in bone marrow to that in serum were between 93% and 105% at that time. MEPM levels were 5.74-0.40 micrograms/g in bones, 20.3-4.55 micrograms/ml in joint fluid and 18.2-4.05 micrograms/g in joint tissues at 30 to 75 minutes after administration. In joint fluid and joint tissues, the concentration above 50% of maximum level in serum were maintained for more than an hour. MEPM is thought to be useful for the treatment of bone and joint infections and also prophylaxis of infections in cases of major surgery of skeletal tissue in the field of orthopaedic surgery.

The pharmacokinetics of meropenem were studied after intravenous infusion in 13 patients grouped according to the impairment of their renal function. Creatinine clearance (CLCR) was greater than 50, 50 to 30, and less than 30 ml/min in groups I, II, and III, respectively. Two other groups, groups IV and V, each comprising four patients with end-stage renal disease (CLCR, < 5 ml/min), were also studied, the former on days off of hemodialysis and the latter on days of hemodialysis. The elimination half-lives of meropenem were 1.54 +/- 0.70 h in group I patients, 3.36 +/- 1.02 h in group II patients, and 5.00 +/- 1.05 h in group III patients. Cumulative urinary excretion accounted for 48.5% of the dose in group I patients and decreased progressively with a decline in renal function. Hemodialysis shortened the elimination half-life of meropenem from 7.0 h to 2.9 h. H-4295, the main metabolite of meropenem, had a peak level in plasma of 0.5 to 1.0 h in patients with renal failure. The level of H-4295 decreased with hemodialysis. The dosing interval of meropenem should be prolonged in a regular proportion to the decline in CLCR (12 h in group II patients and 24 h in group III patients). In patients receiving hemodialysis, dosing after each hemodialysis session is recommended.

The safety and pharmacokinetics of L-627, a new injectable carbapenem antibiotic, were evaluated in healthy volunteers. In single-dose studies, 20, 40, 80, 150, 300 and 600 mg of L-627 were administered by i.v. infusions over 1 hour. Plasma concentration-time profiles were well described with a two-compartment open model. The half-life of elimination from plasma was 1.3 +/- 0.8 (mean +/- SD) hour, and the Cmax and AUC paralleled the doses given. The mean urinary recovery of unchanged L-627 within the first 12 hours was 63.1 +/- 2.7% of the dose. In the multiple-dose studies, 300 mg of L-627 (i.v. over 1 hour) was administered every 12 hours, 11 times in total and 600 mg of L-627 was administered every 12 hours, 9 times in total. No discernible accumulation of the drug in plasma was observed. There were no subjective or objective abnormal findings definitely attributable to the drug except that one subject in one of the multiple-dose regimens (300 mg b.i.d.) showed only a slight elevation of transaminase value, although the elevated value promptly recovered after completion of dosing. No abnormality was observed in the other multiple-dose regimen (600 mg b.i.d.). From these results, L-627 was concluded to be safe and well tolerated.

Evidence of permeation of panipenem through the OprD (D2) channel of Pseudomonas aeruginosa outer membrane was shown by using OprD protein-producing and -nonproducing strains which contained plasmid pHN4, which codes for L-1 beta-lactamase of Xanthomonas maltophilia. Permeation by panipenem was determined by measuring hydrolysis of the carbapenem by beta-lactamase in the periplasmic space. Permeation by panipenem was also determined by counting uptake of [14C]panipenem into P. aeruginosa PAO1 and its OprD protein-deficient mutant, and this permeation of PAO1 was inhibited by L-lysine. These results indicate that panipenem, as well as imipenem, uses the OprD channel, which functions as a specific channel for diffusion of basic amino acids. Panipenem and imipenem showed stronger activities against PAO1 and clinical isolates in human serum than in Mueller-Hinton broth, which contains more amino acids than human serum does. The activities of the carbapenems were reduced by addition of L-lysine to human serum. Similar results were obtained with mouse serum and ascitic fluid. In contrast, such a change in the activities of carbapenems was not observed with an OprD protein-deficient mutant, suggesting that the main reason for the strong activities of carbapenems in biological fluids is a decrease in competition between the antibiotics and basic amino acids for permeation through the OprD channel. Panipenem and imipenem showed much stronger therapeutic efficacies against experimental infections with P. aeruginosa in mice than did the reference antibiotics. Their in vivo activities were more consistent with their MICs in biological fluids than with those in Mueller-Hinton broth.

The pharmacokinetics of meropenem (ICI 194,660) and its open-ring metabolite (ICI 213,689) were studied in 6 healthy volunteers and 16 patients with moderate to severe renal impairment after a single intravenous dose of 500 mg given as a 30-min infusion. Concentrations of unchanged meropenem in plasma and urine were measured by both microbiological and high-pressure liquid chromatographic (HPLC) assays. A good correlation was found between the two techniques. Pharmacokinetic parameters of unchanged meropenem were determined by using the HPLC data. The terminal half-life of unchanged meropenem increased in relation to the degree of renal impairment, being 1.2 h in subjects with normal renal function and 10 h in patients with end-stage renal failure. Total body clearance and renal clearance of unchanged meropenem are linearly related to creatinine clearance. The concentrations of the metabolite in plasma, which are very low in healthy subjects, significantly increased in uremic patients. The apparent half-life of ICI 213,689 increased in uremic patients and was about 35 h in patients with severe renal insufficiency. Meropenem and its metabolite are effectively removed by hemodialysis. The dialysis clearance of the unchanged drug was 81 +/- 22 ml/min. Dosage adjustments of meropenem will be necessary in patients with severe renal impairment.

We performed laboratory and clinical evaluation of meropenem (SM-7338, MEPM), a new carbapenem antibiotics, in pediatric field. Pharmacokinetics of MEPM was examined with 5 patients, at a dose of 10 mg/kg via 30 minutes drip infusion. Mean plasma concentrations at 30 minutes, 1, 1.5, 2.5, 3.5 and 5.5 hours after dose were 18.8, 6.97, 3.62, 1.14, 0.43 and 0.12 micrograms/ml, respectively, with a half life of 0.96 hour. The urine recovery rate in 6 hours was 70.4%. Clinical efficacy of MEPM was evaluated in 36 patients with various infectious diseases. MEPM was administered at doses ranging 9.5 to 30.6 mg/kg/dosage, 3 to 4 times a day, 21/3 to 10 days. Clinical effects were excellent in 24, good in 11, fair in 1, with an efficacy rate of 97.2%. Bacteriologically, all causative organisms except one each of Haemophilus influenzae and Salmonella enteritidis were eradicated, an eradication rate for Gram-positive and Gram-negative bacteria were 100% and 93.3%, respectively. No side effects were observed. Elevations of GOT and/or GPT were noted in 2 patients. From the above results, we believe that MEPM is a highly effective and safe drug for patients with various infectious diseases in pediatric fields.

Meropenem (MEPM), a novel parenteral carbapenem antibiotic, was examined in a cooperative study involving 12 pediatric and 1 neonatologic facilities. The results are summarized as follows. 1. Antibacterial activity Antibacterial activity of MEPM against stock organisms including 31 strains of Streptococcus agalactiae, 14 of Listeria monocytogenes, 4 of Bordetella pertussis and 3 of Neisseria meningitidis ranged from 0.025 to 0.10 micrograms/ml in MIC90's, which were equal or lower than those of control drugs such as imipenem cefazolin, cefotiam, cefotaxime, ceftazidime and latamoxef. MICs against clinical isolates were as follows: In Gram-positive bacteria, MICs were 0.20 micrograms/ml to 6.25 micrograms/ml against 3 strains of Staphylococcus aureus, and 0.025 micrograms/ml or less against 4 of Streptococcus pneumoniae. In Gram-negative bacilli, MICs were 0.10 micrograms/ml to 0.20 micrograms/ml against 3 strains of Haemophilus influenzae and 0.78, 0.10 and 0.78 micrograms/ml, respectively, against one strain each of Enterobacter cloacae, Morganella morganii and Pseudomonas aeruginosa. MIC against 1 strain of Peptococcus saccharolyticus was < or = 0.025 micrograms/ml. 2. Pharmacokinetics Maximum plasma concentrations after intravenous infusion of MEPM over 30 minutes at doses of 10, 20 and 40 mg/kg, respectively, to 3 different groups of 3 children (total 9 cases) were observed at the completion of the treatment. Mean maximum concentrations in the 3 groups were 36.3, 69.5 and 129.8 micrograms/ml, respectively, exhibiting clear dose response. Mean plasma half lives in beta phase were 0.94, 0.86 and 0.94 hours, respectively, exhibiting no difference by doses, and this trend was observed also by HPLC. Urinary excretion rates in the first 6 hours after dose in the 10, 20 and 40 mg/kg groups were 67.3, 65.6 and 68.4%, respectively. Concentrations of MEPM in cerebrospinal fluid were determined in 2 cases of pyogenic meningitis. In 1 case, 500 mg (5.9 mg/kg) of MEPM was infused intravenously over 30 minutes and concentrations on Days 6, 8 and 15 observed at 190, 60 and 100 minutes after respective doses were 0.13, 0.10 micrograms/ml and less than the detection limit. Cerebrospinal fluid-plasma concentration ratio was determinable only on Day 8 and was 2.8%. In another case to which 250 mg (38.5 mg/kg) of MEPM was infused intravenously over 30 minutes, the concentration at Days 6, 7 and 10, 1 hour after the dose were less than the detection limit on day 6, and 2.04 and 2.62 micrograms/ml, respectively on days 7 and 10. 3. Clinical efficacy Clinical efficacies were evaluated in 49 cases and the efficacy rate was 93.9%.(ABSTRACT TRUNCATED AT 400 WORDS)

The pharmacokinetic behavior of panipenem (PAPM)-betamipron (BP), a new carbapenem, in humans was successfully predicted from data collected from six animal species. PAPM and BP were biphasically eliminated from plasma after intravenous (i.v.) administration of PAPM-BP to mice, guinea pigs, rats, rabbits, monkeys, and dogs. Elimination rates of PAPM and BP were correlated with animal size: the larger the animal was, the slower the elimination was. As for PAPM and BP, log-log plots of total plasma clearance (CLtot) versus body weight and log-log plots of distribution volume at steady state (VSS) versus body weight for six animal species were linear, with high correlation coefficients. These allometric equations were extrapolated to predict CLtot and VSS for PAPM and BP in humans. In addition, concentration in plasma-time profiles for humans were predicted by using two-exponent equations fitted to the complex Dedrick plot of animal data. Predicted values for CLtot and VSS for PAPM and BP in humans agreed well with observed values in humans given 750/750 mg of PAPM-BP as an i.v. drip infusion for 30 min. Predicted concentration in plasma-time profiles for humans approximated observed profiles. Thus, the pharmacokinetics of PAPM-BP extrapolated well from animal species to humans when allometric equations and the complex Dedrick plot were used.

The neurotoxic potential of panipenem/betamipron (PAPM/BP), a new carbapenem antibiotic, was compared with that of imipenem/cilastatin (IPM/CS). The drug concentration in cerebrospinal fluid (CSF) at the onset of epileptogenic electroencephalographic (EEG)-activity and the drug distribution into the central nervous system (CNS) were evaluated. Epileptogenic reactions correlated well with drug levels in CSF, but not with drug levels in circulating plasma. The concentration of PAPM in CSF at the onset of epileptogenic EEG-activity was almost twice that of IPM, suggesting that neurotoxic activity of PAPM is about half that of IPM. In addition, in terms of incidence percent for the epileptogenic EEG-activity, PAPM/BP was found to be less toxic than IPM/CS within the dose of 1.0-1.2 g/kg. Concentrations of PAPM in CSF and brain extracellular fluid after PAPM/BP i.v. infusion were comparable with those of IPM after IPM/CS infusion, indicating the similar characteristics of distribution into the CNS for the two antibiotics. From these results of pharmacologic effects and drug distributions, it is suggested that the neurotoxicity of PAPM/BP is less than half that of IPM/CS.

The pharmacokinetics and the clinical effectiveness of meropenem (MEPM) were examined in the field of pediatrics. The results are summarized as follows. 1. A 4-year-6-month-old girl with suppurative meningitis (Haemophilus influenzae) was treated by intravenous drip infusion of MEPM in a daily dose of 29 mg/kg which was divided into 4 dosages, each dosage being infused over 30 minutes, and the drug concentration in cerebrospinal fluid was determined. Upon completion of infusion on the 2nd day of treatment, the drug concentration was 2.52 micrograms/ml, which corresponded to 3.6% of the drug concentration in the blood. 2. MEPM was used in 10 patients, including 3 with suppurative lymphnoditis, 2 with staphylococcal scalded skin syndrome (SSSS) and 1 each with pneumonia, suppurative meningitis, suppurative knee arthritis, facial phlegmon and pyelonephritis. The daily doses ranged from 30 to 117.6 mg/kg, divided into 3 to 4 dosages and administered via intravenous drip infusion over 30 minutes. Clinical responses were evaluated as very good in 7 patients, good in 2 patients and fair in 1 patient, with an efficacy rate of 90%. 3. Isolated pathogens were 2 strains of Staphylococcus aureus, 1 strain of Klebsiella pneumoniae and 3 strains of Haemopilus influenzae. All of the 6 strains were eradicated, with an eradication rate of 100%. 4. In the safety evaluation, none of the patients was observed to have any side effects. Furthermore, no abnormal variations were found in laboratory test data possibly attributable to administration of MEPM.

The pharmacokinetics of meropenem and its ring-opened metabolite (ICI 213,689) were investigated with eight young (20- to 34-year-old) and eight elderly (67- to 80-year-old) healthy male volunteers given single 30-min intravenous infusions of 500 mg of meropenem. All subjects had normal age-correlated glomerular function. The mean terminal half-life of meropenem was 1.27 h in the elderly subjects versus 0.81 h in the younger subjects (P less than 0.001). This and similar increases in mean residence time and area under the concentration-time curve were explained by a reduction in total [139 versus 203 ml/(min.1.73 m2); P less than 0.001], renal, and nonrenal clearances in subjects at advanced ages. The apparent volume of distribution and urinary recovery over 8 h were not significantly altered. With the metabolite, prolonged serum half-life and mean residence time, enlarged area under the concentration-time curve, and lower renal clearance but no significant changes in peak plasma concentration or urinary recovery were found in the elderly. The reduction in the renal excretion rate of meropenem and its metabolite corresponds to the age-associated physiological decline in renal function. The capacity to metabolize meropenem may also be slightly impaired in people at advanced ages. Dose reduction of meropenem should be considered for elderly patients.

Twenty-five children were treated with meropenem (MEPM, SM-7338) and the clinical efficacy and side effects were evaluated. Ages of the patients ranged from 9 months to 11 years. Dose levels of MEPM ranged from 50.4 to 108 mg/kg/day for 4 to 8 days. The 25 patients included 11 pneumonia cases, 4 bronchitis, 6 tonsillitis, 3 urinary tract infections and 1 gingivitis, and they were evaluated for the clinical efficacy of MEPM. Results were excellent in 13 and good in 12 patients. No side effects nor abnormal clinical laboratory test results were observed. The pharmacokinetics of MEPM was studied in 7 patients with ages ranging from 9 to 15 years. The mean plasma peak concentration of MEPM in 5 patients was 36.7 micrograms/ml after dosing 10 mg/kg, and that of 2 patients was 70.0 micrograms/ml after administering 20 mg/kg. These data showed that plasma concentrations of drug depended on dose levels. Average half-life values for the 2 groups (10 and 20 mg/kg) were 0.83 and 0.85 hour, respectively. Urinary recovery rates for the 2 groups (10 and 20 mg/kg) were 64.3% and 81.3%, respectively, in the first 5 hours after administration.

Five healthy volunteers and 18 patients with various degrees of renal impairment received 500 mg of meropenem intravenously as a 30-min infusion. Five dialysis patients were dosed 2 h prior to hemodialysis, and four of them were also dosed between hemodialysis treatments. Plasma and urine samples were collected for up to 48 h and 12 h, respectively. Concentrations of meropenem and its open ring metabolite ICI 213,689 were determined by high-performance liquid chromatography and radioimmunoassay, respectively. The subjects were divided into four groups with glomerular filtration rates (GFR) of greater than 80, 30 to 80, 5 to 29, or less than 5 ml/min. There were linear correlations between the GFR and the rates for total plasma clearance as well as renal clearance of meropenem (group mean values for total clearance of 186, 74, 53, and 19 ml/min/1.73 m2, respectively). In subjects with normal renal function, nonrenal clearance accounted for approximately 20% of total elimination, increasing to about 50% in patients with GFR between 5 and 29 ml/min/1.73 m2. The terminal half-life of meropenem increased from 0.9 h in the healthy volunteers to 6.8 h in patients with end-stage renal disease. The half-life of ICI 213,689 was 2.31 h in the healthy volunteers and increased to 23.6 h in patients with GFR of 5 to 29 ml/min. In patients with end-stage renal disease, half-lives could not be measured, as concentrations were hardly declining during the 48-h observation period. The area under the concentration-time curve for meropenem increased more than 10-fold. Both meropenem and its open ring metabolite were readily dialyzable, with dialysis clearances of 79 and 81 ml/min/1.73 m2, respectively.

Pharmacokinetic and clinical studies on meropenem (MEPM, SM-7338), a new developed carbapenem, were performed and the following results were obtained. 1. Absorption/excretion: Pharmacokinetics of MEPM was studied in 9 children using doses of 10 mg/kg and 20 mg/kg by a 30 minute-drip infusion. Peak plasma levels and plasma half-lives of the 2 doses were 28.4 and 43.0 micrograms/ml, and 0.70 and 0.80 hours, respectively. Their urinary recovery rates were 42.5 to 67.6% and 29.9 to 62.6%, respectively. Cerebrospinal fluid levels and penetration rates of MEPM in a patient with purulent meningitis were 0.66 to 4.01 micrograms/ml and 1.6 to 12.2%, respectively. 2. Clinical study: Forty-nine patients were treated with MEPM at doses exceeding 100 mg/kg/day with purulent meningitis and 30 to 60 mg/kg/day with other infections. MEPM gave "excellent" or "good" responses in 48 cases, an efficacy rate of 98.0%. Only one patient with subdural abscess showed fair response. Diarrhea and rash were observed in 1 case each. Abnormal laboratory test results were noted in 5 patients including elevation of GOT, GPT and eosinophils. In no cases the treatment had to be discontinued.

Pharmacokinetic, bacteriological and clinical studies on meropenem (MEPM) were performed in children. The results are summarized as follows: 1. A total of 16 patients was treated with MEPM. Each dose was 20 mg/kg, and administration was made 3 times daily using 30-minute intravenous drip infusion for 5-28 days. Clinical efficacies of MEPM in 16 patients with bacterial infections (1 with purulent meningitis, 1 with suspected subdural abscess, 2 with suspected sepsis, 4 with pneumonia, 1 with acute maxillar sinusitis, 2 with cervical abscess, 1 with acute gastroenteritis, 2 with skin soft tissue infection and 2 with urinary tract infection) were evaluated as excellent in 7 patients, good in 8 patients and fair in 1 patient with an efficacy rate of 93.8%. Fourteen causative organisms found in 11 patients (Streptococcus pneumoniae in 4, Branhamella catarrhalis in 3, Staphylococcus aureus in 3, Group B Streptococcus in 1, Escherichia coli in 3) were all eradicated. No adverse reactions were observed in any of the 16 patients. 2. MICs of MEPM against 6 clinically isolated bacteria (B. catarrhalis 2, S. pneumoniae 3 and S. aureus 1) from children with bacterial infections were examined. MEPM showed good antibacterial activities. 3. Pharmacokinetic studies: Peak plasma concentrations of MEPM averaged 43.07 micrograms/ml (37.20-46.30 micrograms/ml) at dose of 20 mg/kg administered by 30-minute drip infusion. In the first 8 hours after administration, the urinary excretion rates of MEPM averaged 39.9% of the administered dose.(ABSTRACT TRUNCATED AT 250 WORDS)

The stability of meropenem in the presence of renal dehydropeptidase I (DHP-I) varied extremely with the animal source of the enzyme. Meropenem, compared with imipenem, was rather easily hydrolyzed by DHP-Is from mice, rabbits, and monkeys, while it showed a higher resistance to guinea pig and beagle dog DHP-Is. In addition, meropenem was four times more resistant than imipenem to human DHP-I. The 1 beta-methyl substituent on carbapenems, i.e., meropenem and 1 beta-methyl imipenem, made them considerably more resistant to mouse and swine DHP-Is than the 1-unsubstituted derivatives are.

Pharmacokinetic and clinical evaluations of meropenem (SM-7338, MEPM) were carried out in pediatric patients. The following results were obtained. 1. After 30-minute intravenous drip infusion at a dose of 20 mg/kg, plasma concentrations of MEPM reached their peaks at the end of drip infusion with an average value of 48.8 +/- 3.64 micrograms/ml, and the average plasma half-life was 0.93 +/- 0.21 hour in the beta-phase. After 30-minute intravenous drip infusion at a dose of 10 mg/kg, the average peak plasma concentration was 27.7 +/- 4.33 micrograms/ml and the average plasma half-life was 0.78 +/- 0.20 hour. 2. Urinary excretion rates of MEPM after 30-minute intravenous drip infusion at doses of 20 and 10 mg/kg were 44.8 +/- 4.54% and 40.9 +/- 1.78%, respectively. 3. MEPM was administered to 13 cases (upper and lower respiratory infections, pneumonia and lymphadenitis) at daily doses between 60-90 mg/kg/day divided into 3 dosages using 30-minute intravenous drip infusion. Clinical responses were "excellent" in 12 patients, "good" in 1, hence an efficacy rate of 100% was obtained. 4. Bacteria identified in various disease cases included 12 strains of 5 species, and the eradication rate was 100%. 5. No side effects were observed in any children. Laboratory test results showed abnormalities in 2 cases with elevations of GOT and GPT. These results suggest that MEPM may be a very useful and safe drug for the treatment of pediatric infections.

The transferability of meropenem (MEPM) to cerebrospinal fluid (CSF) was studied employing rabbits with experimental meningitis caused by Staphylococcus aureus. The mean serum concentration was 93.1 +/- 13.5 micrograms/ml at 15 minutes after intravenous administration of MEPM at a dose level of 100 mg/kg. The mean concentration in CSF was maximum at 15 minutes after administration at 4.42 +/- 2.24 micrograms/ml. Pharmacokinetic parameters calculated from these values were as follows: Cmax (CSF/serum) 4.75%, AUC (CSF/serum) 10.4% between 15 and 60 minutes, 13.9% between 15 and 120 minutes and 15.7% between 15 and 180 minutes, T 1/2 for MEPM in CSF: 50.9 minutes, T 1/2 (CSF/serum): 2.19. In comparison to those of imipenem which were obtained in the same way, the transferability of MEPM was similar and in consideration of the antimicrobial potency against the main pathogens of meningitis, it appears worth-while of running clinical trials for this drug.

A new carbapenem antibiotic, meropenem (MEPM), was evaluated for its safety and efficacy in 33 infants and children. MEPM was effective in all the 32 evaluable cases including 4 cases of bacterial meningitis and 5 cases of Pseudomonas aeruginosa infections. The mean half life of plasma concentrations of MEPM was 0.84 +/- 0.09 hours after 30 minutes intravenous drip infusion. Mild diarrhea (2 cases), transient elevation of transaminases (8 cases), and transient eosinophilia (2 cases) were associated with the MEPM therapy, but none of them was problematic. These data suggest that MEPM is safe in infants and children and could be one of the therapeutic agents for severe infections or infections in compromised hosts.

Laboratory and clinical studies on meropenem (MEPM), a new carbapenem antibiotic, were carried out in the field of pediatrics. The results obtained are summarized below. 1. The antibacterial activities of MEPM against clinically isolated organisms in our department were generally high. 2. After 30 minutes intravenous drip infusion of MEPM at a dose of 20 mg/kg to 2 children, the mean peak plasma level of MEPM was 32.7 micrograms/ml at the end of infusion with a mean half-life of 1.45 hours. The mean cumulative urinary recovery rate in the first 6 hours after infusion was 43.6%. 3. Fifteen patients with various bacterial infections were treated with MEPM. The clinical efficacy rate was 100% and the bacteriological efficacy rate was 95.2%. 4. No side effects were observed except in 1 case of mild diarrhea. Some abnormal laboratory test results were obtained, but they were mild with slight elevations of GOT and GPT in 2 cases.

Forty-five children were treated with meropenem (MEPM) and the clinical efficacy and side effects were evaluated. The ages of the patients ranged from 1 month to 9 years and their body weights from 5.2 to 25 kg. Doses given were 17.2-45.5 mg/kg every 6 to 8 hours for 2 to 24.5 days. Those patients who responded to the MEPM treatment included 15 children with pneumonia, 7 with pharyngitis, 3 with cervical lymphadenitis, 3 with cellulitis, 10 with urinary tract infections and 4 with other infections. Among 42 children, the results were excellent in 29, good in 12 and fair in 1. The drug was well tolerated, although slightly elevated serum concentrations of transaminases occurred in 5 patients, eosinophilia in 2 patients, and neutropenia in 1 patient among 45 patients examined. The pharmacokinetic studies on MEPM were done in 6 patients. Their ages ranged from 2 to 9 years and body weights from 14.5 to 23.2 kg. In 4 patients, plasma concentrations at the end of 30 minutes drip infusion of 20 mg/kg were 29.28 +/- 10.29 micrograms/ml and those 3 hours later were 0.49 +/- 0.26 micrograms/ml. Serum elimination half-lives of the drug were 0.66 +/- 0.12 hours in these patients. Excretion rates of this drug into urine in the first 6 hours after initiation of drug administration were 53 and 40% in 2 of these patients. In 2 patients with 35 and 44 mg/kg of drug administration, plasma concentrations were higher than those given 20 mg/kg of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied a newly developed carbapenem, meropenem (MEPM), and obtained the following results. 1. Pharmacokinetics of MEPM in pediatrics was examined in 3 patients. MEPM was injected intravenously at a dose of 16-22 mg/kg by drip infusion for 30 minutes, and its concentrations in serum and urine were determined using bioassay. The average peak value of serum levels of MEPM was 38.4 micrograms/ml and T1/2 beta of MEPM was 1.26 hours. The urinary recovery rate for the first 6 hours after administration was 65.6%. 2. Clinical evaluations of MEPM in pediatrics were done in 14 patients with ages ranging, 1 month to 14 years, with various bacterial infections. Excellent or good clinical responses were observed in all patients, and bacteriological eradication were obtained in 7 out of 8 cases. No serious side effects were observed in any cases, but 2 showed mild and transient GOT, GPT elevations.

Pharmacokinetic and clinical evaluations in pediatrics were made on meropenem (SM-7338, MEPM), a new parenteral dehydropeptidase-1 stable carbapenem used without any inhibitors, at 33 medical institutions. The results are summarized as follows. 1. Pharmacokinetic studies. MEPM at a dose of 10, 20, or 40 mg/kg was administered to 53 children by 30-minute drip infusion. Peak plasma concentrations (Cmax's) and plasma half-lives (T1/2's) of these doses were 28.5, 47.2 and 130.0 micrograms/ml, and 0.80, 0.93 and 0.94 hours, respectively. A clear dose response was observed in Cmax's and T1/2 values were quite similar to those observed in adults. In the first 6 hours after administration, 54.4 to 68.1% of the administered drug was recovered in urine. The cerebrospinal fluid (CSF) levels of MEPM in patients with purulent meningitis were 0.13 microgram/ml at a dose of 6 mg/kg, and 0.64 to 4.22 micrograms/ml at a dose of 29 to 44 mg/kg within day 4 of onset. The penetration rate of MEPM showed an intermediate value among those for other cephalosporin antibiotics. 2. Clinical study. Clinical efficacies of MEPM were evaluated in 389 cases. The most common doses used were 10 to 20 mg/kg/once, 2 to 3 times a day. The maximum dose was 173 mg/kg/day q.i.d. MEPM gave "excellent" or "good" responses in 242 (97.6%) out of 248 cases in which causative organisms were documented and in 134 (95.0%) out of 141 cases in which causative organisms were not identified. Clinical efficacy rates were 100% in 11 patients with purulent meningitis, 85.7% in 7 with septicemia, 98.8% in 173 with pneumonia, and 100% in 65 with UTI. Bacteriologically, 260 strains (96.7%) out of 269 strains were eradicated by MEPM treatment. Eradication rates were 89.2% for Staphylococcus aureus (37 strains) and 100% for Streptococcus pneumoniae (35 strains). The overall eradication rate for Gram-positive bacteria was 94.6%. Among Gram-negative bacteria, 98.3% out of 172 strains were eradicated. The eradication rate of Haemophilus influenzae (73 strains) was 98.6% and Pseudomonas aeruginosa (11 strains) was 90.9%, and all of Branhamella catarrhalis (15 strains), Escherichia coli (42 strains), and Klebsiella pneumoniae (6 strains) were eradicated. Out of 84 cases for which previous antibiotic therapies of 3 days or longer were not successful, MEPM gave "excellent" or "good" responses in 77 cases (91.7%) and excellent bacteriological responses (95.7%).(ABSTRACT TRUNCATED AT 400 WORDS)

One gram of meropenem was administered as prophylaxis to patients undergoing endoscopic retrograde cholangiography (ERC) in a study of the bile pharmacokinetics of this agent. Twenty-four patients were evaluated and a single bile sample was collected from each one during ERC at different time intervals following intravenous infusion. Bile concentrations after the dose ranged from 0.7 to 25.7 mg/L (mean 11.1) and exceeded the MIC90s for the pathogens most commonly associated with biliary tract infections for up to 203 mins. The bile concentrations of 13 patients with biliary tree obstruction were compared with those of 11 patients without obstruction. Bile concentrations in excess of the MIC90s for the predominant pathogens were achieved in both groups; a positive correlation between meropenem bile concentration and the time of dose administration was demonstrable only for the obstructed group. ERC may be a useful technique for biliary pharmacokinetic studies.

Pharmacokinetic and clinical studies in pediatrics were performed on panipenem/betamipron (PAPM/BP), a combined drug of a carbapenem antibiotic (panipenem) and organic ion inhibitor (betamipron) at a weight ratio of 1:1. 1. Plasma levels and urinary excretion were studied when PAPM/BP, at 10 mg/10 mg/kg (4 cases) or 20 mg/20 mg/kg (5 cases), was administered using intravenous drip infusion in 30 minutes to 9 children (4-14 years old). The plasma PAPM level at the end of drip infusion was 30.75 +/- 4.98 micrograms/ml in the cases administered with 10 mg/10 mg/kg and 68.72 +/- 5.73 micrograms/ml in the cases administered with 20 mg/20 mg/kg. Drug concentrations then gradually decreased with half-lives of 1.08 +/- 0.09 hours and 0.98 +/- 0.02 hour, and reached 0.39 +/- 0.14 micrograms/ml and 0.62 +/- 0.06 micrograms/ml, respectively, after 5.5 hours. Plasma BP levels at the end of drip infusion was 18.93 +/- 3.75 micrograms/ml in the cases administered 10 mg/10 mg/kg and 37.09 +/- 2.68 micrograms/ml in the cases administered 20 mg/kg, and half-lives were 0.55 +/- 0.07 hour and 0.61 +/- 0.03 hour, respectively; the plasma BP level could not be determined in any cases after 5.5 hours. Mean urinary recovery rates of PAPM in the first 6 hours after the start of intravenous drip infusion were 33.0 +/- 6.1% in the cases administered 10 mg/10 mg/kg and 21.8 +/- 2.3% in the cases administered 20 mg/20 mg/kg and those of BP were 77.0 +/- 2.4% and 76.6 +/- 7.3%, respectively. 2. When PAPM/BP, was administered at 31.3 mg/31.3 mg/kg thought by intravenous drip infusion in 30 minutes to 1 case of purulent meningitis, PAPM levels were 0.76 micrograms/ml at the end of drip infusion but varied between 0.80 to 1.97 micrograms/ml 30 minutes after the end of drip infusion during 8 days of treatment. 3. PAPM/BP was administered to 43 cases, 47 diseases of bacterial infections in the domain of pediatrics to study its clinical efficacy, bacteriological efficacy and adverse reactions. Single doses were 5.2mg/5.2mg to 31.3 mg/31.3 mg/kg; frequencies of administration were 3 to 4 times a day, and durations of administration were 3 1/3 to 11 days; and total dosages ranged between 1.125 g/1.125 g and 11.0 g/11.0 g.(ABSTRACT TRUNCATED AT 400 WORDS)

Panipenem/betamipron (PAPM/BP), a mixture of a newly synthesized carbapenem antibiotic panipenem (PAPM) and N-benzoyl-beta-alanine, betamipron (BP), was evaluated for pharmacokinetics, in vivo and in vitro antimicrobial effect, and clinical efficacy in pediatric patients. Intravenous drip infusion of either 10 mg/10 mg/kg or 20 mg/20 mg/kg of PAPM/BP for 30 minutes resulted in maximum plasma concentrations of 36.6 micrograms/ml and 92.5 micrograms/ml, half lives (T 1/2 beta) of 1.17 hours and 0.88 hours, and urinary excretion until 6 hours of 29% and 17.7%, respectively. Antibacterial activities of PAPM against Gram-positive cocci and Gram-negative rods isolated from pediatric patients were equal to or slightly stronger than those of imipenem, ceftazidime, cefoperazone, and piperacillin. Clinical effects of PAPM/BP evaluated in 17 patients were as follows; excellent in 8 cases, good in 8 cases, and fair in 1 case. The overall efficacy rate was 94.1%. Elevations of GOT and/or GPT were observed in 2 patients and transient eosinophilia was observed in 1 patient.

Laboratory and clinical studies on panipenem/betamipron (PAPM/BP), a new carbapenem antibiotic, were carried out in the field of pediatrics and the following results were obtained. 1. The antibacterial activities of panipenam (PAPM) against clinically isolated organisms in our department were high overall. 2. After 30 minutes intravenous infusion of PAPM/BP at a dose of 10 mg/10 mg/kg in 1 and of 20 mg/20 mg/kg in 2 children, peak plasma levels of PAPM ranged from 33.21 to 75.66 micrograms/ml at the end of the infusion. The half-lives were 0.81 to 0.93 hours. The cumulative urinary recovery rates in the first 6 hours after the start of drip infusion ranged from 10.7 to 40.4%. 3. PAPM/BP was administered to 16 pediatric patients with various infections. The clinical and bacteriological efficacy rates were both 100%. 4. No side effects were observed. Abnormal laboratory test results were also mild; slight elevation of GOT, GOT/GPT and eosinophylia in 1 each and thrombocytosis in 2.

Panipenem/betamipron (PAPM/BP) is a mixture of panipenem (PAPM), carbapenem antibiotic, and betamipron (BP), N-benzoyl-beta-alanine. The adverse reaction to PAPM of the kidney is reduced by the addition of BP to PAPM which inhibits the anion transport in the kidney tubules. We studied the pharmacokinetics and the clinical efficacies of PAPM/BP in children and we evaluated the antibacterial activities of PAPM by determining MIC values of PAPM in vitro against organisms isolated in our children's hospital from January to December, 1990. 1. Pharmacokinetics 10 mg/kg of PAPM/BP (10 mg PAPM/10 mg BP) was administered intravenously by drip infusion to 7 children. The mean blood concentration of PAPM was 14.8 micrograms/ml at the peak, and the mean half life was 0.9 hours in blood. PAPM was not detected in blood 3 hours after the time when the peak values were attained. 2. Clinical studies 10 mg/kg of PAPM/BP was administered intravenously 3 times a day to 18 cases including 15 of respiratory infections, 2 of otitis media and 1 of sepsis. The clinical efficacies of PAPM/BP were excellent or good in 17 out of the 18 cases. All causative organisms isolated in 5 cases, Methicillin-sensitive Staphylococcus aureus (MSSA) (1 case), Streptococcus pneumoniae (1), Haemophilus influenzae (2) and Branhamella catarrhalis (1) were eradicated in a few days upon the administrations of PAPM/BP. No adverse reactions due to PAPM/BP were observed, but a slight elevation of platelet counts in blood was observed in 1 case, which was normalized soon after the end of the treatment. 3. Antibacterial activities in vitro(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic and clinical evaluations of panipenem/betamipron (PAPM/BP) were carried out in pediatric patients. The following results were obtained: 1. Upon 30-minute intravenous drip infusion at a dose of 20 mg/kg, plasma concentrations of PAPM/BP reached their peaks at the end of drip infusion with average values of 62.94/47.32 micrograms/ml, and their plasma half-lives were 1.00/0.51 hour in the beta-phase. Upon 30-minute intravenous drip infusion at a dose of 10 mg/kg, peak plasma concentrations were 32.10/23.76 micrograms/ml and plasma half-lives were 0.93/0.59 hour. 2. The urinary excretion rates of PAPM/BP after 30-minute intravenous infusion at doses of 20 and 10 mg/kg were 25.09/81.04% and 32.14/84.66%, respectively. 3. PAPM/BP was administered to 18 cases (upper and lower respiratory tract infections, pneumonia and urinary tract infections) at daily doses of 30-88.9 mg/kg/day divided into 3 dosages using 30-minute intravenous drip infusion. Clinical responses were "excellent" in 12 patients, "good" in 5, and "poor" in 1, hence an efficacy rate of 94.4% was obtained. 4. Bacteria identified from various diseases involved 11 strains of 6 species, and the eradication rate was 90.9%. 5. No side effect was recognized in any patient. Laboratory test results showed abnormalities in including 1 case with leukopenia, and in 2 cases with elevation of GOT and GPT.

Pharmacokinetic, bacteriological and clinical studies were performed on panipenem/betamipron (PAPM/BP) in children. The results are summarized as follow: 1. Twelve patients with various bacterial infectious diseases were treated with PAPM/BP. Each dose was 20 mg/20 mg/kg, administered 3 times daily, in 30-minute intravenous drip infusion. Treatments were continued for 5-22 days. Clinical efficacies of PAPM/BP in 12 patients with bacterial infections (1 with suspected sepsis, 5 with pneumonia, 1 with acute maxillary sinusitis, 2 with acute otitis media, 1 with cervical abscess and 2 with urinary tract infection complexed type) were evaluated as excellent in 7, good in 4 and fair in 1, with an efficacy rate of 91.7%. Seventeen causative organisms found in 10 patients (Haemophilus influenzae in 4, Branhamella catarrhalis in 3, Streptococcus pneumoniae in 2, Pseudomonas aeruginosa in 2, Staphylococcus aureus in 1, alpha-Streptococcus in 1, Corynebacterium sp. in 1, Peptostreptococcus micros in 1 and Klebsiella pneumoniae in 2) were eradicated except 2 strains (S. aureus and P. aeruginosa) from 1 patient (patient No. 2). No adverse reactions were observed in any of the 12 patients. 2. MICs of PAPM were examined against 22 clinical isolates (H. influenzae 5, B. catarrhalis 3, alpha-Streptococcus 3, S. pneumoniae 2, Corynebacterium sp. 2, S. aureus 1, P. aeruginosa 1, P. micros 1, Enterobacter cloacae 1, Escherichia coli 1, Group D Streptococcus 1 and Staphylococcus epidermidis 1) from children with bacterial infections. PAPM showed a good antibacterial activity comparable to the activity of cefoperazone (CPZ) against S. pneumoniae strains relatively tolerant to penicillins. However, the activity of PAPM against H. influenzae was somewhat weaker than that of CPZ. 3. Pharmacokinetic studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Unlabelled: Panipenem/betamipron (PAPM/BP), one of the carbapenems, was studied for its absorption and excretion, and clinical efficacy. The following is a summary of the results: 1. Absorption and excretion: Fourteen patients with their ages between 2 years and 14 years were administered with PAPM/BP 10 mg/kg, 20 mg/kg or 30 mg/kg, in 30-minute intravenous drip infusion. Maximum serum levels of PAPM, at dose levels of 10 mg/10 mg/kg, 20 mg/20 mg/kg and 30 mg/30 mg/kg of PAPM/BP, were 27.37 micrograms/ml, 59.3 micrograms/ml, 91.7 micrograms/ml, respectively, at the end of infusion. The half-lives of the 3 dose levels were all within 0.90-0.96 hour. Mean peak serum levels of BP, at dose levels of 10 mg/10 mg/kg, 20 mg/20 mg/kg and 30 mg/30 mg/kg, were 21.77 micrograms/ml, 35.29 micrograms/ml, 50.08 micrograms/ml, respectively, with half-lives of 0.55-0.63 hour. Urinary recovery rates of PAPM in the first 8 hours after administration at dose levels of 10 mg/10 mg/kg, 20 mg/20 mg/kg and 30 mg/30 mg/kg, were 15.9-31.1%, 15.3-36.9%, 11.0-40.5%, respectively, and those of BP during the same time were 33.1-79.1%, 41.3-93.4%, 12.9-94.4%, respectively. 2., Clinical Results: Thirty-nine patients, including 2 with purulent meningitis, 1 with septicemia (suspect), 18 with acute pneumonia, 5 with bronchiolitis, 2 with tonsillitis (unable to receive oral antibiotics), 3 with cervical purulent lymphadenitis, 2 with bacterial enteritis, 6 with urinary tract infections were treated with PAPM/BP at dose levels of 30-100 mg/kg/day. Clinical responses in the patients were excellent or good. Even 2 patients with purulent meningitis were treated with PAPM/BP at dose levels of no less than 20 mg/kg x 3 and 33 mg/kg x 3. Most of respiratory and urinary tract infection cases of moderate severities were treated at dose levels of 30-60 mg/kg/day, i.e., 10 mg/kg x 3 or 20 mg/kg x 3. No adverse reaction was observed. One patient suffered from frequent watery diarrhea but the drug was continued to be administered and the patient recovered quickly. Abnormal laboratory findings were noted, in 2 cases with elevation of platelet, in 1 case with elevation of GOT, in 1 case with elevation of monocyte, in 1 with eosinophilia, in 1 with eosinophilia and decrease in platelet count, in 1 with eosinophilia and elevation of GOT and in 2 with elevation of GOT and GPT, but these abnormalities in the 9 cases were slight and transient.

Panipenem/betamipron (PAPM/BP), a new carbapenem, was studied in dermatology. PAPM/BP was used clinically in the treatment of skin and skin structure infections in a multicenter trial. Fifty three patients were enrolled in the trial. Clinical evaluations were made in 50 patients. Most patients received intravenous infusion of PAPM/BP in a dose of 500 mg twice daily. Other dosages were used in some patients. The overall clinical efficacy rate was 78%. When 15 cases of secondary infections were excluded, the rate was 85.7%. Adverse responses were nausea and/or vomiting in 3 patients, redness with itching in 1 patient, headache or head heaviness in 2 patients and diarrhea in 1 patient. The patient with redness and itching had also nausea and vomiting. This occurred 1 hour after the start of the first infusion of this drug. After the discontinuation of the treatment the symptoms went away on the next day. Abnormalities in laboratory test results were observed in 7 out of 53 patients. One patient with liver cirrhosis and hepatocellular carcinoma developed anemia (RBC 372 x 10(4)/mm3----275 x 10(4)/mm3, Hb 11.9 g/dl----8.8 g/dl, 35.1%----26.0%). Other abnormalities were all mild. Penetration of the drug into skin tissues after intravenous infusion of 500 mg of this drug in skin surgery patients was studied. Skin/serum concentration ratios ranged from 0.20 to 0.97. Skin concentrations were higher than the concentration of PAPM inhibiting 80% of clinical isolates over a period of 6 hours. In rats, skin concentrations were much lower than serum concentrations probably due to the difference in in vivo metabolism of PAPM. A few resistant strains of Staphylococcus aureus against PAPM and imipenem (IPM) were isolated. However, PAPM and IPM showed good antibacterial activities compared to other drugs tested. In conclusion, PAPM/BP is considered to be a useful drug in the treatment of skin and skin structure infections.

The effectiveness and the safety of panipenem/betamipron, new antibiotics of the carbapenems for burn infections, were studied and the following results were obtained: 1. The preparation, 0.5 g/0.5 g, was administered by intravenous drip infusion twice a day to 11 cases of patients with burn infections. In 10 cases for which clinical effects were evaluable, results were rated as "excellent" in 2 cases, "good" in 2 cases and "fair" in 6 cases, with an efficacy rate of 40%. 2. Penetration to the affected tissue was studied in 2 cases. The tissue level of panipenem was 0.20 micrograms/g immediately after the end of drip infusion and 6.86 micrograms/g 60 minutes thereafter. 3. As for the safety, a slight increase in GOT, GPT and Al-P was noted in 1 case; a slight increase in GPT, NAG and beta 2MG was found in 1 case; and a slight increase in GOT, GPT, Al-P and LAP was noted in 1 case, as abnormal variations in laboratory test results.

Panipenem/betamipron (PAPM/BP), a new parenteral carbapenem antibiotic, was investigated with regard to their levels in sera and various tissues collected from patients under orthopedic surgery. The subjects were 17 patients, complaining low back pain and hospitalized for surgical operations. PAPM/BP was administered by intravenous drip infusion for 30 minutes of a dose of 500 mg/500 mg. Serum and cerebrospinal fluid (CSF) specimens were taken from 8 patients at 15-70 minutes after administration and assayed for PAPM and BP levels. Serum, bone, and joint capsule samples where taken from the other 9 cases at 25-127 minutes after administration and assayed. PAPM levels in CSF were considerably lower than those in serum. They were 23.74-1.11 micrograms/ml in sera, 0.31-0.05 micrograms/ml in CSF's during 15 to 70 minutes after administration. PAPM levels were 27.85-2.97 micrograms/ml in sera, 2.54-0.20 micrograms/g in bones, 5.63 and 1.67 micrograms/g in joint capsules during 25 to 127 minutes after administration. BP levels in sera and various tissues were low compared to those of PAPM. These results showed that PAPM was detected at higher levels than 0.2 microgram/g in various tissues, except CSF during 20 to 120 minutes after drip infusion of PAPM/BP 500 mg/500 mg for 30 minutes.

To conduct a basic-clinical study on newly developed panipenem/betamipron (CS-533/CS-443, PAPM/BP) against various infections in pediatrics, a study group was organized and a joint research by 17 institutions and their related hospitals was undertaken. The obtained results are as follows. 1. Blood concentrations and urinary excretion Pharmacokinetics of PAPM/BP in children was studied using 30 minutes intravenous drip infusion of 10 mg/10 mg/kg, 20 mg/20 mg/kg and 30 mg/30 mg/kg, respectively. Maximum blood levels of PAPM/BP were observed at the completion of drip infusion and were 26.72 +/- 8.78 micrograms/ml/18.33 +/- 8.54 micrograms/ml (mean +/- S.D.) with administration of 10 mg/10 mg, 64.80 +/- 18.50 micrograms/ml/38.74 +/- 16.41 micrograms/ml with administration of 20 mg/20 mg and 91.70 +/- 29.42 micrograms/ml/50.08 +/- 22.41 micrograms/ml with administration of 30 mg/30 mg. Dose dependency was noted with these doses. The half-life was about 1 hour for PAPM and about 0.5 hour for BP. As for urinary excretion, PAPM was excreted about 30% and BP about 70% in the first 6 hours after the start of drip infusion. 2. Clinical results Twenty-five cases of exclusion and drop-out were deducted from a total of 391 cases and 8 cases having 2 diseases concurrently were added to the remaining 366 cases, hence 374 cases were evaluated in the study as the subjects of analysis of clinical effects. As for clinical effects in cases where pathogenic bacteria were detected, 215 out of 221 cases were rated as effective or above, hence the efficacy rate of 97.3% was obtained. In cases where pathogenic bacteria were not detected, 145 out of 153 cases were rated as effective or above, thus the efficacy rate was 94.8% which is similar to that in the cases where pathogenic bacteria were detected. The daily dose levels most commonly employed were 30 to 60 mg/kg (as PAPM) administered in 3 divided doses a day, and this regimen method accounted for 52.7% of the total cases, and the efficacy rate with this regimen was 97.0%. As for the bacteriological effect 87 (96.7%) out of 90 strains of Gram-positive bacteria (GPB) disappeared and 136 (91.3%) out of 149 strains of Gram-negative bacteria (GNB) disappeared upon the treatment. The overall bacterial eradication rate for the pathogenic bacteria was 93.4%.(ABSTRACT TRUNCATED AT 400 WORDS)

The prediction of human pharmacokinetics of Panipenem (PAPM), which is a new carbapenem antibiotic, was investigated using animal data. The plasma concentration-time curve after intravenous administration of PAPM in each animal showed biexponential elimination. There were good allometric correlations between pharmacokinetic parameters (CLtotal and Vd,ss) calculated from the plasma concentration in animal species and body weight of experimental animals. Predicted human pharmacokinetic parameters calculated by these allometric equations agreed with the values observed in humans.

The in vitro and in vivo antibacterial activities of meropenem were compared with those of imipenem, ceftazidime, flomoxef, cefuzonam and cefotiam. Meropenem showed a broad antibacterial spectrum against clinical isolates of Gram-positive and Gram-negative bacteria. Against Gram-negative bacteria, with the exception of Acinetobacter calcoaceticus, meropenem exhibited the most potent activity among the drugs tested. It inhibited all 330 strains of Enterobacteriaceae at 0.78 mg/l. Meropenem was sensitive against several cephem-resistant strains of Enterobacteriaceae. Against Pseudomonas aeruginosa, meropenem was four-fold more active than imipenem and eight-fold more active than ceftazidime, with an MIC90 of 0.78 mg/l. The therapeutic effect of meropenem on systemic infection in mice was ten to twenty-fold less than that of imipenem against Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae. However, meropenem was as effective as imipenem on infections of Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Acinetobacter calcoaceticus and Pseudomonas aeruginosa. Meropenem was eliminated from mice plasma two-fold faster than imipenem, with a plasma half-life of 7.6 min. From the above results the authors concluded that meropenem is a promising drug for clinical use.

The pharmacokinetics of IV meropenem (500 mg over 30 min) has been studied in 6 healthy volunteers and 26 patients with various degrees of renal impairment. Blood samples were taken at different times over 24 h in healthy subjects and 36 to 48 h in uraemic patients, and four or five urine samples were collected over 24 or 48 h. Meropenem concentrations in plasma and urine were measured by a microbiological assay. The mean peak plasma concentration of meropenem ranged from 28 to 40 micrograms.ml-1 and was not affected by the degree of renal impairment. The terminal half-life of meropenem was approximately 1 h in subjects with normal kidney function and it was proportionately increased as renal function decreased. A significant linear relationship between total body clearance and creatinine clearance as well as between renal clearance and creatinine clearance was observed. The mean apparent volume of distribution at steady state was not significantly altered in uraemic patients. The mean cumulative urinary recovery of meropenem in healthy volunteers was 77% of the administered dose and it was significantly decreased in patients with renal impairment. Haemodialysis shortened the elimination half-life, from 9.7 h during the predialysis period to 1.4 h during the dialysis period. The dose of meropenem should be reduced in relation to the decrease in creatinine clearance.

The pharmacokinetics and penetration into suction blister fluid of meropenem was investigated after intermittent (10 mg/kg/6 h) and during continuous infusion (10 mg/kg/6 h) in eight healthy male volunteers in a crossover fashion. Concentrations in serum, urine and blister fluid were determined by a HPLC method. The pharmacokinetic parameters in serum (+/- S.D.) T1/2 beta, AUC and clearance after the third dose of intermittent infusion were 62.7 (11.4) min, 43.5 (7.1) mg.h/L and 292.1 (36.8) mL/min respectively. The penetration in blister fluid was rapid and good, with a AUC ratio blister fluid/serum of 84.7 (11.4)%. During continuous infusion, from 12 to 18 h after the start of the infusion, the mean concentration in serum was 6.3 (0.7, S.D.) mg/L and in blister fluid 5.4 (0.7, S.D.) mg/L. The clearance was 338.3 (45.6) mL/min for serum. Urinary recovery was 61.6 (8.7)% after intermittent and 61.9 (6.9)% after continuous infusion.

Imipenem combined with cilastatin and meropenem was given as intravenous infusions of 1 g to eight young, healthy males on two separate occasions. Blood and urine samples were collected for up to 12 h. The terminal half-lives in plasma were 0.98 h and 1.11 h for meropenem and imipenem, respectively. The volume of distribution was smaller for meropenem than for imipenem (12.5 l and 14.4 l, respectively). The plasma clearance for meropenem was 188 (SD 31) ml/min and for imipenem 183 (SD 25) ml/min. Renal clearance was on average 139 (SD 24) ml/min and 135 (SD 11) ml/min, respectively. About 75% of the administered dose of both compounds was eliminated unchanged in urine. Non-renal clearance accounted for approximately 25% of the total clearance for both drugs. The kinetics of meropenem are very similar to those of imipenem given with cilastatin, and meropenem is as stable against renal metabolic degradation as imipenem combined with cilastatin.

Six healthy male subjects who had received imipenem without cilastatin in previous studies, were given 500 mg meropenem as single 30 min intravenous infusions. Plasma and urine samples were collected for 12 h and meropenem and its metabolite were assayed by HPLC and RIA, respectively. The mean plasma half-life of meropenem was 0.8 h, mean plasma clearance 277 ml/min and the mean volume of distribution 20.4 l. The metabolite reached mean peak plasma concentrations of 1.5 mg/l. Renal clearance of meropenem averaged 200 ml/min. The mean urinary recovery of the metabolite was 20% and of unchanged drug 72% of the dose given. The recovery of meropenem ranged from 62.2% to 78.2% and was correlated to the urinary recovery of imipenem when given without cilastatin to the same subjects in previous studies (range 15.2-32.2%, rank correlation coefficient = 0.934). The results indicate that meropenem is much less susceptible to renal metabolism than imipenem. The inter-subject variability observed with meropenem correlates with the extent of urinary recovery of imipenem observed in previous studies with imipenem alone, indicating some susceptibility of meropenem to renal dehydropeptidase-I.

The pharmacokinetics and penetration into a cantharidine-induced inflammatory exudate of meropenem was studied in six volunteers following a single 1-g intravenous dose. Concentrations in plasma, urine, and the inflammatory exudate were determined by a microbiological assay. The mean elimination half-life of meropenem in plasma was 1.1 h, with the concentration in plasma declining from a mean of 23.6 micrograms/ml at 1 h to 0.7 micrograms/ml at 6 h. The inflammatory fluid penetration was rapid (time to maximum concentration of drug in serum, 0.75 h), and the penetration was 111%. The recovery of meropenem in urine at 24 h was 65.4% of the administered dose.

Imipenem serum pharmacokinetics, lung tissue and pericardial fluid concentrations were measured in 10 patients undergoing thoracotomy, following a 1 g intravenous infusion of imipenem-cilastatin. The serum concentrations of imipenem 0.5 h and 4 h after the end of the 40 min infusion were 53.3 (+/- 16.7) and 2.0 (+/- 0.3) mg/l, respectively. The concentration of imipenem in lung tissue at 1 h was lower than in pericardial fluid and at 2.25 h the mean concentration of imipenem in pericardial fluid was 10.5 mg/l, vs. 0.28 mg/kg of lung tissue. Imipenem concentrations in pericardial fluid remained above 5 mg/l, well above the MIC for most pathogens, for 1 h whereas in pericardial fluid the concentration was 10.5 mg/l at 2.25 h.

We used a rabbit model of bacterial keratitis to assess in vivo efficacy of topical imipenem, a highly potent beta-lactam antibiotic with an unusually broad spectrum of activity, including aminoglycoside-resistant Pseudomonas aeruginosa. Albino rabbits received intrastromal injections of 5 x 10(2) organisms of an aminoglycoside-resistant strain of P. aeruginosa. At five hours postinoculation, imipenem (5 mg/ml) therapy was initiated using one drop per 30 minutes for 12 hours. Corneal tissue was then excised for colony forming unit counts. Imipenem was highly effective in reducing colony forming unit counts to zero in comparison to 4.1 x 10(5) organisms for untreated controls. A second regimen beginning 24 hours postinoculation of one drop per hour for 24 hours was also successful in significantly reducing colony forming units vs controls (P less than .05). These data suggest that topical imipenem may have clinical applicability in the treatment of P. aeruginosa keratitis.

Two human volunteer studies were performed with meropenem: a dose proportionality study of 0.25, 0.5 and 1.0 g and a probenecid interaction study. Six volunteers took part in each study. Meropenem was generally well tolerated: One volunteer was withdrawn from the dose proportionality study because of looseness of stool and abdominal pain after a dose of 1.0 g. The plasma concentrations of meropenem were linearly related to dose. The half-life of meropenem was approximately 1 h and the urinary recovery of unchanged drug was 79%. In the presence of probenecid the plasma half-life of meropenem was increased by 33% but the urinary recovery was unaffected.

The rat granuloma pouch model was used to study the penetration of imipenem into inflammatory exudate and its efficacy in an experimental local infection. Rats were given a single intravenous injection of drug via the tail vein at a dose of 40 mg/kg. The peak concentrations of imipenem, ceftizoxime, cefazolin, and cefsulodin in exudates ranged from 10.1 to 12.3 mg/l, except that ampicillin achieved only 5.4 mg/l. Imipenem rapidly reached peak concentration after injection, but the half life for elimination of imipenem from exudate was 77.7 min, which was shorter than that of other beta-lactam antibiotics. Imipenem exhibited more rapid reduction in bacterial growth than cefsulodin in an experimental local infection with Pseudomonas aeruginosa in the pouch model. The results suggested that imipenem was an effective agent in treating the local infection.

We ascertained the pharmacokinetics of imipenem in febrile granulocytopenic cancer patients. The values observed were both different from and significantly more variable than those observed in normal volunteers. Free drug concentrations exceeded the MIC for 90% of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus strains for greater than 6 h. The MIC for 90% of Pseudomonas aeruginosa strains was exceeded for 4 h. Because imipenem induces a 2-h postantibiotic effect in P. aeruginosa, it is promising as single-agent empiric therapy in this setting.