Since methicillin-resistant Staphylococcus aureus (MRSA) is resistant to multiple antibiotics, only a limited number of antibacterial agents shows efficacy against this bacteria. Therefore, combination therapy is often attempted for MRSA infections. Most of the MRSA strains recently isolated, however, have been found to show very high resistance, and some of the antibiotics which had previously been effective have been failing to produce good responses in increasing numbers of patients. Thus, the drugs used for combination therapy in MRSA infections need to be reevaluated.
We assessed the bacteriological efficacy of cefotiam (CTM) plus minocycline (MINO) therapy against MRSA in an in vitro system (CTM) shows relatively strong antibacterial activities against MRSA with moderate resistance, and MINO shows strong antibacterial activities against highly resistant MRSA.
1. Against MINO-susceptible MRSA strains, CTM + MINO demonstrated potent antibacterial activities at MINO concentrations of MIC or sub-MIC levels, irrespective of the MIC of CTM against MRSA strains being tested.
2. Against MINO-resistant MRSA strains (strains for which MICs of MINO exceeded the upper limit of the clinically expected plasma MINO level), CTM + MINO showed no significant antibacterial activity. These results suggested that the effect of this combination was dependent on the antibacterial activity of MINo.Therefore, the usefulness of this combination in patients with MRSA infections can be predicted based on susceptibilities of involved strains to MINO.
3. The potent antibacterial effect of this combination against MINO-susceptible MRSA strains was considered to be the result of damage to the cellular membrane by MINO and the subsequent antibiotic effect of CTM. The activity of the combination was also reflected by the FIC indices.

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We performed an in vitro assessment of the antibacterial activity of therapy with cefuzonam (CZON) plus minocycline (MINO) against methicillin-resistant Staphylococcus aures (MRSA) infections.
1. Studies using MINO-susceptible and MINO-resistant MRSA strains suggested that the antibacterial activity of CZON + MINO was dependent on the antibiotic action of MINO, similarly to the case with cefotiam (CTM) +MINO.
2. The antibacterial activity (including the FIC index) of this combination was slightly inferior to that of CTM + MINo.However, the time course of antibacterial efficacy of CZON+MINO in MRSA pretreated with MINO was comparable to that of CTM + MINO.
3. CZON+MINO appeared to be a very useful combination in patients with mixed infections due to MRSA and Gram-negative bacteria.

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To investigate single dose toxicity of cefepime (CFPM diHC1/L-arginine blend), the test drug was administered to rats [Crj: CD (SD)] of both sexes at dose levels of 500, 1,000 and 2,000 mg/kg using intravenous continuous infusion or subcutaneous injection, and to male beagle dogs at 1,000 and 2,000 mg/kg using intravenous continuous infusion. As the control, two additional groups of each animals were given either saline or L-arginine alone which was used in the test formulation to adjust pH values of CFPM diHCl solutions.
The obtained results are summarized as follows:
1. Rats dosed with 2,000 mg/kg CFPM through intravenous continuous infusion showed slightly decreased spontaneous physical activity. One male rat dosed with L-arginine alone via continuous infusion also showed slightly decreased activity. Slight to severe inflammatory reactions at injection sites including sloughing of the tail were prominent at doses of 1,000 or 2,000 mg/kg of CFPM, or L-arginine alone. Average body weights of rats in the test groups of either sex were comparable to the controls in all of the dose groups of the same sex during the 14-day test period.
2. Rats receiving 2,000 mg/kg CFPM in single subcutaneous injection showed slightly diminished activities. Slight to moderate reactions occurred around the injection site (viz., hardening, depilation, scab-formation and necrosis) in rats injected any of the 3 doses of CFPM. Though body weight gains were slightly retarded in male rats receiving 2,000 mg/kg CFPM during the last half of the observation period, such weight gain retardation was not observed in rats of other dose groups.
3. No death occurred in any groups of any injection routs or dose levels during the 14-day observation period in rats. Necropsy showed that the dose-related changes were restricted to the injection sites without showing other abnormalities.
4. Dogs to which 1,000 or 2,000 mg/kg of CFPM or L-arginine alone was administered via intravenous continuous infusion showed vomiting, flushing, swelling of face and decreased physical activities. Tachypnea, staying in a prone position, walking with staggering gait, persistent urination, depression of stimulation response, discoloration of mucus membranes of oral cavity and excessive salivation resulted when CFPM was administered at 1,000 or 2,000 mg/kg. These transient signs of toxicity disappeared in 15 to 60 min after the completion of dosing with L-arginine alone, or in 6 hours with CFPM. Though the recovery of these signs of toxicity was slow when CFPM was administered compared to the dose of L-arginine alone, no difference was observed between the 2 groups of dogs administered with 1,000 and 2,000 mg/kg CFPM. No drug-related difference was detected in body weight changes, amounts of food consumed or by pathological examinations.
Based on these results, the single dose toxicity of CFPM in rats administered via intravenous continuous infusion appeared to be low, and it was comparable to that via single dose subcutaneous injection. Lethal doses of CFPM in rats were higher than 2,000 mg/kg by either route of administration under the experimental conditions employed in this study. Since no significant toxicity was detected in dogs dosed with 2,000 mg/kg of CFPM using intravenous continuous infusion, the lethal dose for dogs seems higher than this level.

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In order to investigate the toxicity of cefepime (CFPM, BMY-28142 diHCl/L-arginine blend upon repeated subcutaneous dosing), the test article was administered to Crj: CD (SD) rats of both sexes at daily dose levels of 150 (low dose), 500 (intermediate dose) and 1,500 (high dose) mg/kg/day by subcutaneous route for 28 days.Two additional groups of rats were given either saline (negative control) or L-arginine (vehicle control).Doses were equally divided and administered twice each day with an interval of approximately 5 hours between the 2 doses of a same day.A half of rats in negative control and high dose groups were retained for examination during one-month recovery period.
The results obtained are summarized as follows:
1. Upon general observations, it was found that drug-related changes were restricted to the injection sites. Depilation and scab-formation of the injection sites were noted in high dose rats of both sexes and intermediate dose females. No deaths occurred during the study.
2. Slightly depressed body weight gains were observed for high dose males during the latter part of the dosing period.
3. Slightly lower food consumptions were noted for intermediate and high dose males at Week 1.
4. Slightly higher water consumptions were generally detected for high dose rats during the dosing period.
5. Hematological examinations revealed that a slight decrease in the average value of relative lymphocyte counts and a slight increase in the average value of relative segmented neutrophil counts were evident for high dose males.These findings might be attributable to the inflammatory reactions at the injection sites.
6. Chemical examinations of the blood showed that average values of GOT and GPT increased slightly in high dose males and females, and average values of total protein, albumin and triglyceride decreased slightly in high, intermediate and/or low dose males.Decreased values of total protein and albumin appeared to be related to the tissue damage at the injection sites.
7. In urinalysis, lower urinary pH values occurred more frequently in the vehicle control and high dose group compared to the low and intermediate dose groups.
8. At necropsy at the end of the dosing period, a slightly increased incidence of subcutaneous hemorrhage was noted among high and intermediate dose rats of both sexes.Enlargement of the caecum noted in high dose females was considered drug-related and was due to alteration of gut flora.
9. At the end of the dosing period, average values of absolute and/or relative organ weights of the kidneys of high dose males and females were slightly higher than those from corresponding control rats.Slightly lower average absolute and relative organ weights of the liver were observed only among high dose males.
10.In light microsopic observations, drug-related inflammatory changes such as hemorrhage, cell infiltration, crust, fibrosis and thickening of the epidermis were prominent at the injection sites for high and/or intermediate dose rats.Similar findings were also observed for vehicle control males. Dilatation of the caecum and colon noted for some high and one intermediate dose females was considered to be drug-related.
11.In electron microscopic observations, no drug-related changes were found in the liver and the kidney of high dose males and females.
12. In toxicological parameters examined in this study, all the drug-related changes seemed to be generally reversible and returned to normal ranges of values after the recovery period. Based upon the above results, since slightly depressed body weight gains for males and slightly increased serum GOT and GPT values for males and females were noted at 1,500 mg/kg/day of CFPM in this study, the no-effect dose level of CFPM was estimated to be 500 mg/kg/day in the one-month repeated subcutaneous dose toxicity study for rats disregarding local irritation at the injection sites.

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Cefepime dihydrochloride (CFPM) was administered subcutaneously daily at doses of 0, 150,500 and 1,000mg/kg for 63 days prior to mating and during mating to male Crj: CD (SD) rats and for 14 days prior to mating and during mating, as well as periods of gestation and lactation to female SD rats. Saline and L-arginine hydrochloride (L-arginine) were used as control articles. Daily doses of test and control articles were equally divided and administered twice a day (b.i.d.). The results obtained are summarized as follows:
1. Soft stool was observed for both male and female Fo rats at CFPM 1,000mg/kg at the first week of administration period.Further, depilation of injection sites was found in 7 males and 12 females at the same dose level.
2. Body weight gains were suppressed in male Fo rats from Day 28 to 63 of administration period at CFPM 1,000 mg/kg.Moreover, food consumption was reduced in Fo female rats during the first week of administration period at all dose levels of CFPM.
3. CFPM failed to affect the reproductive performance in both male and female Fo rats.
4. Kidney weights were increased in both male and female Fo rats and adrenal weights were augmented in male Fo rats at CFPM 1,000 mg/kg. On the other hand, cecal enlargement were observed for Fo dams treated with CFPM.However, these changes were not considered to be unique to this drug, because they have been described with most antibiotics in this species and appears to be results of modifications in gut flora.
5. Prenatal developments in F1 fetuses were not affected by CFPM.
6. CFPM failed to affect delivery status of Fo dams or survival and lactation indices in F1 pups.
7. CFPM did not affect postnatal differentiations, developmental behaviors, learning ability and memory, spontaneous motor activity or emotionality in F1 rats.
8. Body weight gains and food consumption in both male and female F1 rats were not affected by CFPM.
9. CFPM did not alter the organ weights in both male and female F1 rats.
10. There were no significant differences between drug treated animals and controls regarding the reproductive performance and delivery status of F1 rats.
11. Influences on survival indices, body weights and organ weights were not apparently observed for F2 pups even at CFPM 1,000mg/kg.
Based on the reproductive and developmental indices, the no-effect dose level of CFPM under the present experimental condition was estimated to be 1,000mg/kg/day against dams (F0) and their offspring (F1).

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General pharmacological properties of cefepime (CFPM), a new injectable semisynthetic cephalosporin and its metabolite N-methylpyrrolidine-N-oxide (NMP-N-oxide) were studied in laboratory animals.The results obtained are summarized as follows:
1. CFPM reduced spontaneous locomotor activity but potentiate the anesthesia at the highest dose in mice.Furthermore, significant hypothermia and analgesia were observed at the same dose in mice.No effects were found on the other CNS function in mice and rats or on EEG activities in rabbits.
2. Muscle relaxant activity was not observed in mice treated with CFPM even at the highest dose.
3. CFPM had no effect on the intestinal smooth muscle and did not show any antagonism against some smooth muscle contracting drugs.
4. The respiration, blood pressure, heart rate and ECG were affected by CFPM.Those changes, however, might have been principally caused by L-arginine blended with CFPM product.
5. No effect of CFPM on the intestinal movement or gastric secretion was found even at the highest dose of CFPM.
6. The pH neutralizer L-arginine caused alterations in the renal function and electrolyte metabolism but CFPM did not.
7. Whole blood clotting time tended to be lengthened by CFPM at the highest concentration but this effect seemed to have been caused by L-arginine.Other parameters of the coagulation system or red blood cell resisitance were not affected by CFPM.
8. NMP-N-oxide, a metabolite of CFPM, had almost no effect on any of the tested parameters except for its slight effect on the circulatory system.
These findings indicate that CFPM has scarcely any pharmacological properties which might be leading to severe adverse reactions in clinical use.

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Ceftriaxone (CTRX), a new third generation cephalosporine, was investigated upon once daily administration for its clinical efficacy and safety on respiratory tract infections in patients with advanced ages.The results are summarized as follows:
1. Clinical responses to CTRX of 48 cases of advanced age patients with respiratory tract infections were good with an efficacy rate of 89.6%.
2. Adverse reactions to CTRX were mainly exanthema in 7 cases (14.6%).
3. Serum levels of CTRX were determined in 4 cases after intravenous drip infusion of 2g CTRX.Serum levels were analyzed by one-compartment model.There was no evidence of accumulation of CTRX in the patients with advanced ages.

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The efficacy and the safety of meropenem (MEPM), a newly developed carbapenem antibiotic, were investigated in 150 patients with severe infections complicated with hematopoietic disorders.
1. Clinical responses in 132 patients who were evaluable for effectiveness were excellent in 33 patients, good in 45, fair in 10 and poor in 44, with an efficacy rate of 59.1%.
2. The efficacy rate in patients who had previously been treated with the other antibiotics was 51.2%, while that in patients who had not been thus treated was 62.9%.
3. The efficacy rate in patients whose neutrophil counts increased during the therapy with MEPM was higher than that in patients whose neutrophil counts did not increase. The efficacy rate in patients whose neutrophil counts during the therapy were below 100/mm3 was 48.1%.
4. Out of 150 cases, side effects were observed in 4 patients, 3 with eruption and 1 with jaundice. Abnormalities in laboratory test results on liver functions were noted in 8 patients.
These results indicate that MEPM is an effecive and safe antibiotic for the treatment of severe infections in patients with hematopoietic disorders.

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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 summerized as follows.
1.Pharmacokinetic studies
MEPM at a dose of 10, 20, or 40mg/kg was administered to 53 children by 30-minute drip infusion.
Peak plasma concentrations (Cmax's) and plasma half-lives (T 1/2's) of these doses were 28.5, 47.2and 130.0, μg/ml, and0.80, 0.93 and 0.94 hours, respectively.A clear dose response was observed in Crnax's and T 1/2 values were quite similar to those observed in adults.
In the first 6 hours after administration, 54.4to68.1%of the administered drug was recovered in urine.
The cerebrospinal fluid (CSF) levels of MEPM in patients with purulent meningitis were 0.13g/ml at a dose of 6mg/kg, and 0.64 to 4.22μg/ml at a dose of 29 to 44mg/kg within day 4μ of onset.The penetration rate of MEPM showed an intermediate value among those for other cephalospolin antibiotics.
2. Clinical study
Clinical efficacies of MEPM were evaluated in 389 cases.The most common doses used were 10 to 20mg/kg/once, 2 to 3times a day.The maximum dose was 173mg/kg/day q.i.d.
MEPM gaveexellentorgoodresponces 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 gavee xellentorgoodresponces in 77 cases (91.7%) and exellent bacteriological responces (95.7%).
3. Side effects and laboratory test results
Among 403 cases, 6 symptoms were noted as side effects in 5 cases including diarrhea, rash, watery stools and loose stools.
Abnormal laboratory results occurred in 58 cases including increases in GOT, GPT, β-GTP, LDH, LAP and eosinophil counts, and decrease in neutrophil counts.
Based on these results, we concluded that the standard dose of MEPM in pediatrics would be 10to20mg/kg/once, 2to3 times a day.The dosage may be altered according to symptoms.In conclusion, MEPM is a useful and safe drug for the treatment of various infections in children including severe infectious diseases such as purulent meningitis and septicemia.

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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 17.2-45.5mg/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 concetrations 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 20mg/kg were 29.28±10.29μg/ml and those 3 hours later were 0.49±0.26μg/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 44mg/kg of drug administration, plasma concentrations were higher than those given 20mg/kg of the drug. Serum elimination half-lives were 0.5 and 0.62 hours, and excretion rates into urine in the first 6 hours were 70% in both cases.
The cerebrospinal fluid level at 2.8 hours after a dose was 0.37μg/ml on the 5th day of treatment in 1 patient who was partially treated for bacterial meningitis receiving 43.5mg/kg of the drug every 6 or 8 hours. Its level at 2 hours after the dose was 0.37μg/ml on the 11th day of treatment in another patient with viral meningo-encephalitis who was given the drug at 45.5mg/kg every 6 hours.
The influence of MEPM on the fecal flora was studied in 7 patients. The disappearance of Enteribacteriaceae and Bifidobacterium was noted in 1 infant during a treatment with the drug. In 6 other patients, the decrease of Enterobacteriaceae was noted but the number of Bifidobacterium was preserved rather well during the drug administration regardless of the presence of the drug in the feces.

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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 38.4μg/ml and T1/2β of MEPM was 1.26 hours. The urinary recoverly 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.

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Meropenem (MEPM) was evaluated for its efficacy and safety. The following results were obtained.
MEPM was given to 12 patients with infections: 5 with pneumonia, 1 with bacterial meningitis, 2 with pharyngitis, 4 with skin and soft tissue infections. Therapeutic responses were excellent in 5, good in 4 and fair in 3, with an efficacy rate of 75%.
Adverse reactions were not noted. No abnormalities were shown in laboratory data.
It has been concluded that MEPM is a useful drug for the treatment of bacterial infections in children.

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We studied the clinical efficacy of meropenem (SM-7338, MEPM), a new parenteral carbapenem β-lactam antibiotic, in pediatric field. Thirteen patients with 2 months to 8 years and 8 months of ages, with acute infectious diseases were administered with doses at 39.3 to 76.7 mg/kg/day of MEPM intravenously. The diagnoses consisted of 7 respiratory tract infections, 1 sepsis, 2 orbital cellulitis, 1 parotid abscess, 1 lymphadenitis and 1 pyoderma.
The clinical efficacy rate was 84.6% (11/13), and the bacteriological eradication rate was 71.4% (5/7).
Clinical laboratory examinations revealed 1 patient with eosinophylia and another with anemia. No other side effects attributable to this drug were observed.
It appears that MEPM is a useful antibiotic for moderate to severe acute bacterial infections in children.

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Bacteriological and clinical studies have been performed on meropenem (MEPM, SM-7338), a newly developed carbapenem antibiotic, in the pediatric field.
1. Antibacterial activities of MEPM against 24 clinical isolates were determined. MEPM showed excellent activity against Gram-positive bacteria including Staphylococcus aureus and Gramnegative bacteria, especially Escherichia coli and Branhamella catarrhalis.
Against Haemophilus influenzae, MEPM had a higher activity than imipenem and flomoxef, but had a lower activity than piperacillin and cefoperazone.
2. Clinical efficacies of MEPM were evaluated in 32 cases with bacterial infections. A poor efficacy was observed in 1 patient with phlegmon but excellent or good efficacies were obtained in other 31 patients with tonsillitis (1), pneumonia (17), UTI (12), or SSSS (1). The overall efficacy rate was 96.9%.
All strains except 1 of S. aureus were eradicated by the administration of MEPM, and a high eradication rate of 95.8% (23 out of 24 strains) was obtained.
3. No side effects were obsereved in 35 evaluated cases. As abnormal laboratory test results, elevated GOT, elevated GPT, eosinophilia and neutropenia were noted in 4, 4, 4 and 2 patients, respectively.
4. Influences on blood coagulation parameters were studied. PIVKA II was elevated upon administration of MEPM in some cases, but no changes in ATT, TT, HPT or Fbg were observed during the treatment.
Based on the above results, it has been concluded that MEPM is a safe and effective drug to use in the treatment of pediatric infections. The usual recommended dosage and administration should be 10 to 20 mg/kg of MEPM at a time, using intravenous drip infusion, 3 times a day.

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