Cefuroxime (CXM) is a new injectable cephalosporin stable against β-lactamases.The results of preclinical and clinical studies so far carried out in Japan on cefuroxime are summarized in this paper.
1. CXM is stable to various kinds of β-lactamases except the one produced by P.vulgaris GN76 (RICHMOND type Ic).Reflecting this action, CXM has been shown to have antibacterial activity, not only against organisms which respond to conventional cephalosporins, but also against Citrobacter, Enterobacter, Hafnia, and Indole positive Proteus which are resistant to conventional cephalosporins.
2. After an intravenous or an intramuscular injection, satisfactory blood levels of CXM are attained with the half-life about1hour, and CXM is excreted into urine via kidney in an active form. Transfer of CXM to tissues or various body fluids such as bile, cerebrospinal fluid, prostatic fluid, etc., is also satisfactory.
3. Of the total826evaluable cases treated in the open clinical study, 243cases (29%) were assessed as ‘excellent’ and 404 (49%), as ‘good,’ and the efficacy ratio (‘excellent’ and ‘good’) was as high as78%.
4. In a double-blind comparative study vs.cefazolin in patients with respiratory or urinary tract infections, CXM was proven to be superior to CEZ in either the infection, both in terms of clinical efficacy and global utility.
5. Incidence of side effect was very low.Of the total1,057cases treated in the open and boubleblind clinical studies, side effects, mostly skin hypersensitivity and pyrexia, were noted only in26cases (2.5%).

View full abstract

We previously reported patients with Mycoplasma pneumoniae pneumonia in whom M.pneumoniae acquired resistance to erythromycin or josamycin during the treatment with erythromycin or josamycin. The resistance developed to a macrolide antibiotic was accompanied by the cross-resistance to other macrolides.The results indicated that the infection with M.pneumoniae resistant to macrolides is possibly encountered. We determined the susceptibility to erythromycin and josamycin in 237 isolates of M.pneumoniae recovered from 237 patients up to 1976 and concluded that the infection with M. pneumoniae resistant to erythromycin or josamycin was not observed.As josamycin recently has been widely used for the therapy of M. pneumoniae infections in Japan, the infection with M. pneumoniaeresistant to josamycin has become more possible.In the present study we determined the josamycin susceptibility of M.pneumoniae isolates recovered from 1980 to March, 1981.
Isolates served for the determination of the minimum inhibitory concentration (MIC) of josamycin were 137 isolates of M.pneumoniae recovered from 113 patients with M.pneumoniae infections.
The prelintinary experiment with the use of Mac strain of M.pneumoniae showed that the microtiter method gave the same value of the MIC as the tube method and so the microtiter method was used in the present study.The plates were observed every day during the incubation.As read on the day when the control wells without josamycin first changed in color to yellow (pH6.4), showing a rich growth, the minimum concentration of josamycin which inhibited the growth, showing no color change, was termed as MIC. The minimurn concentration of josamycin which inhibited the growth during a month's incubation was termed as the final minimum inhibitory concentration (FMIC).
For the M.pneumoniae isolates, the MIC of josamycin ranged from 0.0031 to 0.024 μg/ml and the FMIC from 0.0061 to 0.05 μg/ml. The MIC was 0.0031 μg/ml for 2 isolates (1.5%), 0.0061 μg/ml for 25 isolates (18, 2%), 0.0122 μg/ml for 76 isolates (55.5%), and 0.024 tiglinl for 34 isolates (24.8%), revealing that the MIC was 0.0122 μg/ml or less in more than a half of the isolates tested.The FMIC was 0.0061μg/ml for 9 isolates (6.6%), 0.0122μg/ml for 38 isolates (27.7%), 0.024μg/ml for 85 isolates (62.0%), and 0.05μg/ml for 5 isolates (3.6%), revealing that the FMIC was0.024μg/ml in more than a half of the isolates. The FMIC was similar or close to the MIC in values.All of the isolates were sensitive to josamycin.The results reveal that M.pneumoniae resistant to josamycin as well as other macrolides has not yet caused infections in man.
Of 21 patients from whom M.pneumoniae was isolated twice or more, 6 patients had received erythromycin more than 7 days.As we previously reported, the development of the resistance to erythromycin in M. pneumoniae is accompanied by the cross-resistance to josamycin as well as other macrolides. The MIC of josamycin for the isolates from the 6 patients was not different more than 3 times between the isolates before and after the erythromycin therapy, showing that all of the isolates were sensitive to josamycin.The results indicated that the resistance to macrolides did not develop in the 6 patients after the erythromycin therapy.

View full abstract

The rate of isolation of anaerobic bacteria from various clinical specimens became more and more significant in recent years, and anaerobic bacteria, especially Bacteroides play an important role in the opportunistic infections or polymicrobial infections. The purpose of this paper is to study1) the annual changes of the incidence of anaerobes from clinical sources, 2) the antimicrobial susceptibility of the recent isolates of various anaerobic bacteria, 3) the changes in incidence of the drug-resistant strains, and4) the, β-lactamase activity from Bacteroides species to clear the reason, for the prevalence of drug-resistant strains of Bacteroides.
1) The annual changes of the incidence of anaerobic bacteria in Juntendo University Hospital for the past 16 years (from 1965 to 1980) shoW that there has been a gradual increase in the incidence of nonsporulating Gram-negative rods including Bacteroides species, and nonsporulating Gram-positive rods (Propionibacterium, Lactobacillus, and Eubacterium). With selected types of specimens, a much higher incidence of recovery of anaerobes had been obtained from the intraabdominal and the obstetrical and gynecological infections.I also summarized the clinical background of 10 cases ofanaerobic bacteremia for the past 2 years.In 7 cases, B. fragilis was isolated as a single culture, or as one of the mixed cultures. The major focus of the infections seemed to be abdomen with previous surgery, and most important prognostic factors appeared to be the underlying diseases, surgery, or previous use of antibiotics.
2) Approximately 440 strains of anaerobic organisms, isolated from clinical specimens during January 1979 and April 1981, were selected to test the antimicrobial susceptibility to 20 antimicrobials. The minimal inhibitory concentrations (MIC) were obtained by an agar plate dilution methods, proposed by the Japanese Society of Chemotherapy.
the Japanese Society of Chemotherapy. Benzylpenicillin and ampicillin were susceptible in vitro, but many or most strains of B.fragilis were resistant to these 2 agents.Other penicillins were not always as active as benzylpenicillin and ampicillin. Cephalosporins were also quite active against many anaerobes, but most had relatively poor activity against Bacteroides.Ceftizoxime was demonstrated to be more active against B.fragilis than the other β-lactam antibiotics. Many anaerobes are now resistant to tetracycline, however, doxycycline and minocycline were more active than tetracycline. Chlorarnphenicol and thiamphenicol had excellent in vitro activity against all anaerobes. Clindamycin was represented distinctly more active than erythromycin and lincomycin, and had the greatest activity against anaerobes in all drugs. But, clindamycin-resistant strains have increased in Bacteroides species.Metronidazole also had excellent against anaerobes except for a certain Gram-positive organisms (Propionibacterium and Lactobacillus).
3) I determined the MIC ‘break point’ between susceptible and resistant strains, by the distribution of MIC for 16 years of observation.And under the criteria for resistance, the changes in incidence of resistant strains of Peptococcus, Peptostreptococcus and Bacteroides were observed.
Against Peptococcus and Peptostreptococcus, a marked increase of resistant strains was recognized in tetracycline during these periods.No resistant strains were recognized to the other drugs against Peptococcus.Against the Peptostreptococcus strains, however, slight or moderate increase in resistant strains was observed in benzylpenicillin, ampicillin and erythromycin.For the Bacteroides species, remarkable changes in resistant strains were observed in almost antimicrobials.

View full abstract

Normal mice acutely and chronically infected with the S-273 strain of T.gondii, were treated with acetylspiramycin (ASPM) alone, 8 mg/mouse/day, per os, or in combination with an immunopotentiator (CSP-II), 10 mg/mouse/day, intraperitoneally, or sulfamethopyrazine (SMPZ), 2mg/mouse/day, per os, for a period of 4 weeks.
In the acute cases, a 99.4% cyst reduction was obtained with ASPM alone and no cysts were seen in the brains of mice treated with ASPM in combination with CSP-II or SMPZ.The organisms were significantly eradicated in the brain and heart tissues of mice trated with ASPM alone or in combination with CSP-II or SMPZ as shown by subinoculation to normal mice and the negative latex hemagglutination titers of the recipient mice.
In the chronic cases, a cyst reduction of 52.4% was obtained with mice treated with ASPM in combination with ap-n.A cyst reduction of 34.6%, 32.9% and 20.8% was obtained in the ASPM alone, CSP-II alone and ASPM in combination with SMPZ treated groups, respectively.A comparative clearing of the organisms in the heart tissues of mice treated with ASPM in combination with CSP-Hwas obtained compared to the other treatment groups but not in the brains of all groups.

View full abstract

The combination therapy of β-lactam and aminoglycoside antibiotics is now evaluated to be very effective in severe bacterial infections.Amikacin, one of aminoglycoside antibiotics, has antibacterial activity to gentamicin resistant bacteria.Then we tried to use the combination therapy of amikacin and β-lactams in 20 cases with severe bacterial infections, including 2 cases of bacteremia etc.Fifteen cases out of them failed to cure by previous antibitics treatment.With a few exception, amikacin was administered daily 200 mg in 2 devided intramuscular injections. β-Lactams were administered twice a day by intravenous drip infusion, but dose and kind of β-lactams were decided by attending doctors.
Clinical efficacy of this combination therapy was classified in 4 degrees: excellent, good, fair and poor.Clinical efficacy rate (excellent and good results) in all cases was 75%.This is equally effective, compared with the newly sold antibiotics.
Elevation of serum GOT and GPT levels was seen in 2 cases in whom large amount of PCs was given.
As a conclusion, it was indicated that the combination therapy of amikacin and β-lactam in the regular dose was sufficiently effective and useful for the therapy of severe bacterial infections.

View full abstract

A total of 42 patients who were suffering from respiratory tract infections were treated with cefoxitin, and the following results were obtained.
1.Out of 32 patients clinically evaluated, excellent or good responses were observed in 30 patients (94%).
2.Presumed causative organisms were isolated in 14 patients.The organisms were eradicated in 11 patients and the eradication rate was 79% (11/14).The number of the organisms decreased or unchanged in 1 patient each.In other 1 patient the pathogenic agent was replaced with other agents during the course of treatment.
3.As for the side effects, skin eruption was observed in 3 patients.One patient received drugs other than cefoxitin concomitantly that might have caused the eruption.Another patient had an allergic history to many antibiotics.In 4 patients slight elevations of S-GOT and S-OPT were observed but improved soon after the completion of cefoxitin treatment.In 1 patient an elevation of serum creatinine was observed but this was not attributed to the administration of cefoxitin.
4.From the results stated above, cefoxitin is considered to be a safe and effective antibiotic which can be one of the first-choice antibiotics for the treatment of respiratory tract infections.

View full abstract

C-AMOX was administered to adult patients of acute bacterial skin infection at the dosage of 500 mg 2 times a day after meals in the morning and in the evening.
Evaluation was done in 4 grades, i.e.excellent, good, fair and poor.
Of 42 cases treated, excellent was marked in 11 cases and good was in 14 cases.Percentage of excellent and good results was 59.5%.Fair results being included, the percentage rises to 83.3%.As subjective side effects, stomach trouble (including stomachache) were observed in 2 cases and diarrhea, perleche, rash, nausea and loss of appetite were each 1 case.

View full abstract

Experimental and clinical studies on ceftizoxime (CZX), a newoephalosporin derivative, were carried out and the following results were obtained.
1.The minimal inhibitory concentrations of CZX, cefazolin 4CEZ), cephalothin (CET), cefotiam (CTM) and cefmetazole (CMZ) against Gram-positive cocci (31 strains) and Gram-negative rods (169 strains) isolated from the patients with oral infections were determined.CZX, though somewhat less active against Gram-positive cocci than the other oephalosporins, was the most active of the antibiotics tested against Gram-negative rods.
2.The mean serum levels in 19 patients who received I g of CZX by intravenous drip infusion for 1 hour were as follows: 19.6μg/ml 30 minutes after the start of intravenous drip infusion, 52.2μg/ml after 1 hour, 25μg/ml after 1.5hours, 20.3μg/ml after 2 hours, 7.9μg/ml after 4 hours, 3.5μg/ml after 6 hours.The mean peak tissue levels of CZX after 1 g dose by intravenous drip infusion for I hour were14.3μg/g (n=5) in gingiva and 8.5μg/g (n=2) in bone marrow at the end of intravenous drip infusion.
3.CZX was administered to 17 patients with various infections in the oral surgical field at daily dose of1-2g for3-6 days.The therapeutic effect was as follows: ‘excellent’ in 6 cases, ‘good’ in 9, ‘fair’ in 1 and ‘poor’ in 1. The final rate of effectiveness was 88.2%.
No adverse reaction was observed except for 2 cases of slight elevation of S.GPT.

View full abstract

1. Clinical pharmacology
The pharmacological studies on tobramycin (TOB) were studied in clinical patients. The peak serum levels following intravenous drip infusion (i.v.d.) administration of TOB 60mg were4.62mcg/ml in 0.5 hour and 4.09 mcg/ml in 1 hour respectively which achieved at the discontinuance of the drug. In 1 case, the concentration in serum and urinary recovery were determined when 60 mg of TOB was given twice a day in i.v.d. at an interval of 5 hours. The peak serum level was 4.11mcg/ml at the first administration, and 4.96mcg/ml at the second.No significant accumulation of the drug was observed. The urinary recovery of TOB during0-11.5hours was44%.
2. Clinical results
Tobramycin was administered in a dose of 60-120mg once or twice a day by i.v.d.against18cases of chronic complicated UTI.The duration of treatment varied but generally 5 days.An overall excellent or moderate effect was seen in81%.
3. Clinical chemistry
The clinical abnormal values from laboratory tests of renal, hepatic function and peripheral hematology in patients treated with TOB were obsereved in 2 cases.In 1 case BUN increase (17.6→23mg/dl) and in the other GOT and GPT elevations (GOT 24.1→u→66.7u, GPT 26.2u→68.8u).The abnormal values, however, returned to normal within 2 weeks after the discontinuance of the drug.
4. Clinical tolerance
Adverse reactions were encountered in 2 cases.The 1 case yielded skin rash with itching in the second day after therapy.The other case complained of general itching with mild headache 2 days after starting therapy.In above cases TOB treatment was discontined, soon after appearing these symptoms.The complete recoVery was recognized within 2 days in each case.
5. Summary
Based on the clinical pharmacology and clinical studies, intravenous drip infusion administration of tobrarnycin can be given safely and effectively in treatment of chronic complicated UTI.

View full abstract

Clinical trials of9, 3-diacetylmidecamycin (MOM), a new macrolide antibiotic were carried out on 46 pediatric patients of 1 month to 11 years old with infections (acute pharyngitis12, acute tonsillitis 1, acute bronchitis14, asthmatic bronchitis10, acute pneumonia 1, primary atypical pneumonia2, Mycoplasma pneumonia 4 and pertussis2).As a rule, MOM was given orally at a daily dose of20-40mg/ kg divided into 3 times.The clinical results were excellent in 5patients, good in 21, fair in 7 and poor in 13 and the efficacy rate was 56.5%.Side effects were observed in 4 patients (diarrhea, exanthema, urticaria and eosinophilia, 1patient respectively).
MOM is easy to take and a useful antibiotic for treating pediatric patients with bacterial infections, in particular, respiratory tract infection caused by Mycoplasma pneumoniae.

View full abstract

1. The dry syrup of MOM was administered orally to 17patients mainly with heart deseases at doses of 10mg/kg and 20mg/kg.In 17cases, the serum level was measured and in 4cases, the urinary excretion rate including the metabolites of MOM.
2. The mean maximal concentrations were 0.54mcg/ml at30minutes for the group of 10mg/kg treatment and 0.33mcg/ml at 1hour for the group of 20mg/kg treatment.The dose response was not observed obviously in both groups.
3. In each of the cases, the sum of excretion rates of metabolites in the 24-hour urine was about 1%.
4. MOM was administered clinically to 39cases with respiratory tract infections and the overall efficacy rate was 85%.
5. In this study, 5 strains of S.pyogenes were isolated and the eradication rate was60%.
6. Although severe side effects were not observed, gastrointestinal abnormalities like diarrhea and vomiting were seen in 3cases.
7. Any pediatric patient did not refuse taking.

View full abstract

Cefotetan (CTT) is a new parenteral semisynthetic cephamycin-type antibiotic with a broad antibacterial spectrum against both Gram-positive and Gram-negative bacteria. Against wide varieties of Gram-negative bacteria, particularly including indole positive Proteus, S. marcescens, Enterobacter sp.and C.freundii CTT was more highly active than cefmetazole, cefoxitin and cefazolin. The50%inhibition doses (ID₅₀) of CTT against E.coli, K. pneumoniae, P. mirabilis, indole positive Proteus and S.marcescens were by far superior to those of the 3 other antibiotics. The antibacterial activities of CTT were bactericidal and were little affected by addition of horse serum and by variation in pH of the medium, in inoculum size and in type of culture media.Model infections in mice against Gram-positive and Gram-negative bacteria were studied. The therapeutic effects after subcutaneous injection of CTT against various Gram-negative bacterial infections were superior to those of cefmetazole, cefoxitin and cefazolin.

View full abstract

An acute toxicity study on netilmidn (NTL) and gentamicin (GM) was carried out in mice and rats, subacute toxicity of NTL was tested in comparison with GM in Sprague-Dawley (SD) rats. The ariimals were treated with NTL (12.5, 25, 50 and 100 mg/kg/day) or GM (50 and 100 mg/kg/day) intramuscularly for 30 days and followed by 35-day recovery test without treatment.
The following results were obtained.

View full abstract

A chronic toxicity of netilmicin (NTL) was tested in Sprague-Dawley rats.The animals were treated with NTL (7.5, 15, 30and60mg/kg/day) intramuscularly for26weeks and a9-week recovery test was also carried out.

View full abstract

The subacute toxicity of netilmicin (NTL), an aminoglycoside antibiotic, in Beagle dogs was compared with that of gentamicin (GM).NTL at dose levels of1.5, 6, 25and100mg/kg/day and GM at dose levels of6and 25mg/kg/day were given intramuscularly for30 days.Control dogs received physiological saline.After the termination of the administration period, 2 males and 2 females among 5 males and 5 females from each group* were retained for a30-day recovery period. (For the GM 25mg/kg/day group, 1male and1female were retained for the recovery test)

View full abstract

Teratological study on netilmicin (NTL), a new aminoglycoside antibiotic, was carried out in Sprague-Dawley rats (Slc: SD).NTL was administered intramuscularly to female rats from day 7 to day 17 of gestation at the dosages of12.5, 25, 50and100mg/kg.
The decrease of food intake at the dosage of50mg/kg and more, and the resultant depression of maternal body weight gain at the dosage of100mg/kg were observed in dams receiving NTL.
The depression of fetal growth, such as body weight and ossification of the sternebrae and caudal vertebrae, were detected in the animals treated with50and100mg/kg of NTL.However, NTL failed to induce the external, visceral and skeletal anomalies in fetuses.
Also, NTL did not cause any significant changes in birth rate, s uckling rate, weaning rate, body weight, postnatal development, behavior and reproductive performance in F₁.
These results suggest that NTL has no adverse effect on rat fetuses and F₁ generation at the dosage of 25 mg/kg or less.

View full abstract

Fertility study on netilmicin (NTL), a new aminoglycoside antibiotic, was carried out in Sprague-Dawley rats (Slc: SD).NTL was administered intramuscularly to male rats at the daily dose of12.5, 25, 50and100mg/kg from 6 to 15 weeks of age for 9 weeks before mating and during the mating period, and to10weeks old female rats at the daily dose levels from day 14 before mating through day 7 after gestation.
The increase of kidney weight at the dose of12.5mg/kg and more, the decreases of food intake and body weight were observed in treated male rats.The decreases of food intake and body weight were observed in female rats treated with the dose of 50 and100mg/kg.
No dose-related changes were observed in mating and fertility ratios of parent animals, numbers of corpora lutea and implantations, fetal mortality, external, visceral and skeletal anomalies, body weight, body length and tail length of fetuses.
Therefore, it can be concluded that maximum non-toxic dose level of NTL on rat fertility is100mg/kg.

View full abstract

Perinatal and postnatal study on netilmicin (NTL), a new aminoglycoside antibiotic, was carried out in Sprague-Dawley rats (Slc: SD).NTL was administered intramuscularly from day17of gestation throughout day20after delivery at the daily dose of12.5, 25, 50and100mg/kg.
Water intake of pregnant and nursing dams was increased in the animals treated with50mg/kg or more of NTL.
The increase of cecum weight was observed in F₁ animals in all treated groups at3weeks of age.
However, birth rate, suckling rate, weanling rate, body weight, postnatal development, behavior and reproductivefunction remained within normal ranges in all treated groups.

View full abstract

Teratological study on netilmicin (NTL), a new aminoglycoside antibiotic, was carried out in New Zealand White rabbits.NTL was administered intramuscularly from day6to day18of gestation at the dose levels of 12.5, 35and100mg/kg.
The decrease of food intake, water intake and depression of body weight were observed in the pregnant animals treated with100mg/kg of NTL.
Body weight and tail length of fetuses were significantly decreased in the animals treated with35and100 mg/kg compared with those in saline control or vehicle control groups.However, no dose-related changes or anomalies were detected in mortality, extarnal, visceral and skeletal examinations of fetuses.
Thus, it can be concluded that NTL has no adverse effect on rabbit fetuses.

View full abstract

To10cases with respiratory infections, 200mg, twice daily, of netilmicin was administered without other antibiotics and the following results were obtained.

View full abstract

1) Netilmicin was administered to24subjects with infectious diseases.It was found as theresult that8remarkably effective, 8effective, 2slightly effective, 3non-effective and3undetermined effect cases were observed.The rate of effectiveness better than ‘effective’ was76%.
2) Side effect was examined;urinary findings, renal and hepatic functions, peripheral blood pictures, auditory tests, etc.were all normal, and no abnormality due to the preparation was found.

View full abstract