We assessed the bacteriological emcacies of cefotiam (CTM) plus imipenem (IPM) and CTM plus vancomycin (VCM) therapies against methicillin-resistant Staphylococcus aureus (MRSA) in an in vitro system. The results are summarized as follows.
1. It appeared that the bacteriological emcacies of CTM+IPM therapy against MRSA strains were difbrent against different target MRSA strains. In other words, the FIC indices of CTM+IPM were distributed in a wide range of≤0.5->2.0. The strains showing MIC levels of≤8μg/ml in IPM concentrations showed a strong correlation with FIC index values of≤0.5, and the strains showing the MIC level of≥128μg/ml in IPM concentration showed a strong correlation with FIC index values of>2.0. Hence, the strains showing FIC indices≤0.5 were considered to be newbom strains with penicillin-binding Protein 2'(PBP-2'), those showing FIC indices>0.5-≤2.O were considered to be strains with increasing production in PBP-2', and those showing FIC indices>2.0 were considered to be strains with increasing productions in both PBP-2'and PBP-m2. In strains with FIC indices higher than 2.0, the 2 drugs may possibly share the action mechanism and the activity center thus they compete with each other.
The above results indicated that the bacteriological emcacy of CTM+IPM therapy could be expected only for MRSA strains showing the MIC level of≤8μg/ml at IPM concentrations and that overconfidence in the bacteriololgical emcacy of CTM+IPM therapy due to the difference in the point action of the 2 drugs should be avoided.
2. Results with CTM+VCM against MRSA strains suggested that the combined bacteriological efficacy of both drugs might not be obtained. This was considered to be due to the competition in the mechanism of action of these 2 drugs. Additionally, if 2 drugs may possibly share the mechanism of action, thus may compete against each other, antagonism may exist. Therefore, it is desirable to be prudent in the combined use of VCM andβ-lactams including CTM in patients with MRSA infections.

View full abstract

We assessed the bacteriological efficacies of cefotiam (CTM) plus arbekacin (ABK) and CTM plus minocycline (MINO) therapies against methicillin-resistant Staphylococcus aureus (MRSA) in an in vitro system. The results are summarized as follows.
1. Both of CTM+ABK and CTM+MINO demonstrated almost perfect antibacterial activities against MRSA strains at ABK and MINO concentrations of MIC levels as clinically expected plasma ABK or MINO levels, and also showed antibacterial activities at ABK or MINO concentrations of sub-MIC levels. But no results suggesting antagonism were obtained.
2. The potent antibacterial effect of CTM+ABK or CTM+MINO against MRSA strains was considered to be the result of damage to the cellular membrane of target strains by ABK or MINO with ABK or MINO concentrations at MIC or sub-MIC levels and by the subsequent antibiotic effect of CTM.
3. A combination of drugs which are different from each other in mechanisms of action and points of action is likely to show a consistent antibacterial effect, but a combination of drugs which are competitive to each other because they share mechanism and point of action possibly cause antagonism.

View full abstract

Antimicrobial activities of cefmetazole (CMZ)and cefazolin (CEZ) in combination were studied against clinical isolates of Staphylococcus aureus (9 methicillin-sensitive and 47 methicillinresistant strains) using the checkerboard MIC method and the disc diffusion test using Mueller Hinton agar with or without addition of 4% NaCl.
MICs of CMZ and CEZ in dividually against 9 methicillin-sensitive strains (MSSA) were 0.78-1.56μg/ml and 0.39-0.78μg/ml without 4% NaCl,and 1.56-3.13μg/ml and 0.39-0.78μg/ml with 4% NaCl, respectively. In combination of CMZ and CEZ, the MICs of CMZ and CEZ against these MSSA decreased to 0.012-0.39μg/ml and 0.10-0.20μg/ml without 4% NaCl, and 0.20-0.78μg/ml and 0.20-0.39μg/ml with 4% NaCl, respectively, showing minimum FIC indexes of 0.385 to 1.013. Minimum FIC indexes≤0.5 were seen in 7 out of 9 strains.
MICs of CMZ and CEZ individually against 47 methicillin-resistant strains (MRSA) were 3.13-100μg/ml and 3.13-400μg/ml without 4% NaCl, and 6.25-50μg/ml and 50-400μg/ml with 4% NaCl, respectively. In combination of CMZ and CEZ, MICs of these drugs against MRSA were reduced to0.10-50μg/ml and 0.39-200μg/ml without addition of 4% NaCl and 0.39-12.5μg/ml and 3.13-100μg/ml with 4% NaCl, respectively. Minimum FIC indexes observed were 0.047 to 0.625, and those with values≤0.5were observed in 43 out of 47 strains.
By the disc dimlsion method, between the CMZ disc and CEZ disc, asynergistic interaction against MRSA was well observed. In addition, discscontaining both drugs showed a greater inhibitory zone diameter than discs containing the equivalent amount of CMZ or CEZ alone.
These in vitro observations reported here suggest that the use of CMZ and CEZ in combination is more effective than the use of these drugs individually for the treatment of MSSA and slight to moderate resistant MRSA infection, as well as for surgical prophylaxis.
TherefOre, further study was carried out to assess the synergistic enhancement of antimicrobial activity of CMZ and CEZ in combination using discs containing various amounts of these drugs at various ratios. Using discs containing CMZ/CEZ (20μg/10μg), disc inhibitory zone diameters against MSSA and MRSA were well correlated negatively with MICs of CMZ or CEZ in combination. From inhibitory zone diameters obtained with these combination discs, enhanced MICs of CMZ or CEZ in combination can be assessed.

View full abstract

The author evaluated in vitro effects of combinations of antibiotics against 27 clinical isolates of highly-fosfomycin (FOM)-resistant, methicillin-resistant Staphylococcus aureus (MRSA). In combinations of FOM and cephems (CEPs), MICs of CEPs were decreased by FOM significantly, and synergistic effects were observed when the MIC of FOM was below 50μg/ml. Combinations of imipenem/cilastatin (IPM/CS) and CEPs, however, was superior to those of FOM and CEPs in terms of synergistic effects. In these combinations, good synergism was found when the MIC of IPM/CS was below 25μg/ml and those of CEPs were relatively low. In combinations of aminoglycoside and CEPs, no apparent synergism was observed. Most significant synergistic effect was achieved in the combination between IPM/CS and cefamandole. We believe that both fractional inhibitory concentration indices and achievement rates of effective serum concentrations should be taken into account to determine an effective combination of antibiotics.

View full abstract

The transferability of vancomycin (VCM) to cerebrospinal fluid (CSF) was studied employing rabbits with experimental meningitis caused by Staphylococcus aureus.
VCM was administered intravenously for 30 minutes at a dose level of 30mg/kg. Serum concentration reached a maximum of 75 3.80μg/ml (mean±S. E.) at the completion of administration (i. e., 30 minutes) and CSF concentration reached a maximum of 2.4±0.39μg/ml at 60 minutes.
Pharmacokinetic parameters calculated from this concentration-time curve were as follows: Cmax (CSF/Serum) 3.21%, AUC (CSF/Serum) 2.39% between 15 and 60 minutes, 3.99% between 15 and 120 minutes, and 4.40% between 15 and 150 minutes. T 1/2 for VCM in CSF: 143 minutes, T1/2 (CSF/Serum): 2.09.
Based on this investigation, VCM appears to be effective in the treatment of meningitis caused by MRSA (Methicillin-resistant S. aureus).

View full abstract

A solution of 0.5g of meropenem (MEPM) in 100ml 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 15.4μ g/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 5.74-0.40μg/g in bones, 20.3-4.55μg/ml in joint fluid and 18.2-4.05μg/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.

View full abstract

Flomoxef (FMOX) was administered as an initial treatment for chorioamnionitis complicating possible spontaneous abortion or premature delivery and preterm PROM (premature rupture of the menbranes), and the clinical effectiveness of the drug, and the usefulness of fetal fibronectin (FFN) as a diagnostic marker of premature delivery were evaluated.
1. Clinical effects of drip infusion of FMOX (2-4g/day) with and without tocolysis for the treatment of chorioamnionitis were evaluated in 43 patients with possible spontaneous abortion or premature delivery and those with preterm PROM (n=43). Changes in the FFN level in the vaginal secretion were also studied in 11 patients.
2. It was possible to prevent premature delivery in 7 (26.9%) of 26 patients, and the latent period of preterm PROM was longer than 8 days in 6 (46.2% ) of 13 patients.
3. The FFN level decreased slightly in patients for whom FMOX was effective, and the outcome was satisfactory in those whose FFN levels were less than 200 ng/ml. However, the outcome was poor in those whose FFN levels were higher than 1,000 ng/ml. These findings suggest that changes in the FFN level in the vaginal secretion reflect the clinical course of chorioamnionitis as do changes in CRP.

View full abstract

Imipenem/cilastatin sodium (IPM/CS) which is a broadspectrum agent against both Grampositive and-negative bacteria was used in combination with fosfomycin (FOM) as a secondline chemotherapy for severe infections associated with hematologic disorders. FOM was partnered with IPM because FOM may enhance the bacteriocidal effects of IPM when given as pretreatment to IPM/CS therapy.
Fifty two patients were treated with IPM/CS plus FOM. Of them, 41 were evaluated for effectiveness. Eleven patients were not evaluated: 4 were treated with a combination of other regimens such as cefixime, γ-globulin, G-CSF and a large dose of methyl predonisolone; 2 were given IPM/CS plus FOM as a first choice; 3 were observed to have gastrointestinal side effects such as nausea which led to the discontinuation of the combination therapy; and 2 were thought to be suffering from not infectious but tumor fever.
An excellent response was observed in 15 (36.6%) patients and a good response in 10 (24.4%), for a overall efficacy rate of 61.0%. Efficacies was 71.4% (5/7) in patients with sepsis, and 60.0% (9/15) in patients whose peripheral granulocyte count was below 100/μl before chemotherapy.
The elimination rates of Gram-positive and-negative bacteria were 57.1% (4/7) and 75.0% (6/8), respectively. In particular, 75.0% (3/4) of Pseudomonas aeruginosa identified were eliminated.
Two patients who suffered from tumor fever, 2 who did not receive chemotherapy before the combination chemotherapy and 3 who did not receive a full course of the combination chemotherapy because of side effects, were included in the final evaluation of safety.
Side effects were observed in 18 of 48 patients (37.5%). In 1 patient, skin eruption occurred 3 days after the initiation of the combination chemotherapy. In 17 patients, gastrointestinal symptoms such as nausea and vomiting were identified after a few days of IPM/CS plus FOM administration. Degree's of the symptoms were mild, however. Therefore, the treatment was not withdrawn. No abnormal laboratory results such as eosinophilia, liver disfunction or renal disfunction were observed.
These results show that IPM/CS plus FOM is effective as a second-line combination chemotherapy for the treatment of severe infections in patients with hematologic disorders.

View full abstract

We report that the results of clinical studies on ceftriaxone (CTRX) in respiratory tract infections (RTIs). Clinical efficacies and side effects of CTRX were as follows;
1. Clinical efficacies of CTRX in a total of 61 cases with RTIs were excellent in 11 cases, good in 23, fair in 11, poor in 12 and unknown in 4. Thus the overall clinical efficacy rate was 59.6%. In cases of patients with lung cancers, the efficacy rate was 42.9%.
2. Clinical efficacy rates with once daily dosage were 50.0% with a dose level of 1g CTRX and 54.8% with that of 2g CTRX.
3. Side effects were observed in 2 cases (3.1%) and laboratory abnormalities were observed in 1 case (1.6%). They were not serious, however.
These data suggest that CTRX is one of the useful cephalosporins in treatment of RTIs.

View full abstract