The MICs of 407 strains of Oral Streptococci, collected and measured in clinical tests of new antimicrobial agents conducted during the period from September, 1989 to June, 1991, were studied. The following 9 antimicrobial agents were used: ampicillin (ABPC), cefteram (CFTM), cefuroxime (CXM), cefpodoxime (CPDX), cefdinir (CFDN), cefixime (CFIX) cefaclor (CCL), ofloxacin (OFLX) and levofloxacin (LVFX). We have come to the conclusion that ampicillin has a higher MICs than previously. On the other hand, ester-type cephems, cefteram pivoxil (cefteram) cefuroxime axetil (cefuroxime) and cefpodoxime proxetil (cefpodoxime), proved to have low and excellent MICs. Cefdinir (non-ester-type) also showed a low, and excellent, MICs.

View full abstract

We devised the “Auto-simulator Shionogi”(AS apparatus) which uses a microcomputerto automatically regulate the concentration time curve to simulate that in human serum in order to evaluate the bactericidal activity of antibiotics under conditions closely resembling those in the human body. We have used the AS apparatus in conducting many experiments to evaluate the bactericidal activities of various antibiotics.We encountered some problems, but these were solved as described below.
1) An abnormally high density of bacteria occasionally appeared in the tubesupplying the medium, which had its tip immersed in the medium of the culture bottle.These bacteria led to false “regrowth”in the time-kill curve. To prevent this problem, the tube tip was reformed so that it was not immersed in the medium.
2) During the auto-simulation experiment, bacteria that attached to the inner surface of the culture bottle were released into the culture medium, and abnormal time-kill curves resulted.To avoid this problem, the inner surface of the bottle was rinsed with culture medium containing a high concentration of antibiotics.
3) Some bacterial strains formed biofilm-like lumps in the sampling tube. When this occurred, random time-kill curves were obtained and the reproducibility of the data could not be assured.
In using the AS apparatus, the artifacts should be taken into considerartion when interpreting the data obtained.

View full abstract

The formation of biofilm is a cause of chronic infection because biofilm blocks the diffusion of antibacterial agents, preventing them from reaching bacteria. To assess the permeability of antibacterial agents through Pseudomonas aeruginosa biofilms, we devised a simple method using an Intercell^® and a multi-well plate. P. aeruginosa cells were inoculated in an Intercell^® placed on a brain heart infusion agar plate. Biofilm was formed on the membrane filter of the Intercell^® during incubation at 37°C for 3 days. Scanning electron micrographs showed that the biofilm formed was about 100 μm in thickness and consisted of bacterial and spongy glycocalyx layers. The biofilmformed Intercell^® was placed in a multi-well plate, and the surfaces of the biofilm were coated with agar to prevent peeling. A solution of antibacterial agent was added to the Intercell^® and phosphate buffer was poured into the outside of the Intercell^® until the levels of the solution on both sides were equal. After incubation at room temperature for 24 hours, the concentration of the antibacterial agents outside the Intercell^® was measured by bioassay. The diffusion rate of gentamicin (200μg/ml) in the presence of biofilm was 42% of that in the absence of biofilm. In addition, the slime prepared from P. aeruginosa lowered the antibacterial potency of gentamicin, and its bactericidal activity decreased with an increase in the concentration of the slime. These findings suggest that biofilm forms a barrier to diffusion of gentamicin, attributable to binding of the drug to alginate which is a primary constituent of P. aeruginosa biofilm. On the other hand, in the case of ceftazidime, no change was observed in the diffusion rate regardless of the presence or absence of biofilm. Furthermore, addition of P. aeruginosa slime did not affect the potency of ceftazidime and its bactericidal activity, suggesting that ceftazidime diffuses freely through biofilm.

View full abstract

We investigated the antimicrobial chemotherapy-enhancing effects of recombinant human granulocyte-colony stimulating factor (rG-CSF) in treating experimental pneumonia caused by Legionella pneumophila serogroup 1 (strain No.80-045). Polymorphonuclear leucocytes (PMNLs) increased in circulating blood and the pulmonary air spaces of sublethally infected (1×10⁴ CFU/body) guinea pigs following administration of rG-CSF (100μg/kg twice a day). The increased number and heightened function of PMNLs contributed to a reduction in the number of bacteria in the lung, leading to a significantly increased survival rate in guinea pigs with lethal pulmonary infections (5×10⁶ CFU/body), when combinated with ceftazidime, which has strong in vitro antimicrobial activity against L. pneumophila but is in effective in Legionella infection because of its lower cell penetration. These findings show the importance of PMNLs in nonimmunospecific defences against Legionella pneumonia, and suggest the usefulness of rG-CSF in combination with antimicrobial therapy.

View full abstract

We assessed the pharmacokinetics and dosage regimen of vancomycin in patients with renal insufficiency.
1) Vancomycin (VCM), 500 mg, was administered to healthy volunteers and patients with varying degrees of impaired renal function by 60-minute drip infusion. Serum levels of VCM after a single dose were assayed by FPIA and urinary levels by bioassay. Pharmacokinetic parameters were determined using a two-compartment model. In healthy volunteers, mean T_1/2 (β) was 3.08 h and mean β was 0.233/h. As the degree of renal insufficiency became more severe, T_1/2 (β) became more prolonged and β decreased. The mean 24-h urinary excretion rate was 96.3% in the healthy volunteers and decreased in accordance with the severity of the renal insufficiency.
2) To plan the dosage regimen, β was selected as a parameter which varied in accordance with the degree of impaired renal function as determined on the basis of creatinine clearance. The appropriateness of this regimen was confirmed in a multiple-dose study.

View full abstract

The effectiveness of miconazole (MCZ), an imidazole-derivative, anti-fungal agent, was evaluated in patients with systemic mycosis and states associated with hematologic malignancies including acute leukemia, chronic myelogeneous leukemia, myelodysplastic syndrome, malignant lymphoma and myeloma in which it was suspected. Plasma β-D-glucan levels, differences between Txicolor test and Endospecy test levels, were also followed. Thirteen patients with systemic mycosis and 23 patients with conditions suspected of representing fungal infections were treated with MCZ, 800-1, 200 mg daily i. v. Excellent-good responses were observed in 5 (38.5%) of the 13 patients with a definitive diagnosis of mycosis and in 11 (47.8%) of the 23 patients suspected of having a fungal infection, for an overall efficacy rate of 44.4%(16/36). Plasma β-D-glucan levels correlated well with the efficacy of MCZ in 10 out of 12 patients. however, there were several patients with low plasma β-D-glucan levels throughout the entire course. Plasma β-D-glucan levels were low (below 15 pg/ml on repeated determinations) even in 2 cases of pulmonary candidiasis and disseminated deep-seated mycosis diagnosed on the basis of several tissue histologies at autopsy. The results indicate that MCZ is an effective agent for the treatment of severe systemic fungal infections in patients with hematologic disorders. Deep-seated mycosis cannot be ruled out even when plasma levels of β-D-glucan are low.

View full abstract

Methicillin-resistant Staphylococcus aureus (MRSA) was detected in 27 samples from 135 patients with hematological malignancies admitted to our division from June, 1989 to July, 1992. Isolated MRSA was identified as the cause of infection in 16 cases. MRSA isolated patients with lymphoid malignancy tended to be infected more frequently than those with non-lymphoid diseases. Skin and soft tissue infections showed the highest incidence and these were always accompanied by small skin injuries including those resulting from small surgical treatment. The microbiological effect of used antibiotics on superficial and deep organ infections was 92% and 30%, respectively. Even if cases to which vancomycin or arbekacin, were administrated and those with adequate granulocyte counts were included, the prognosis of patients with MRSA infection in deep organs was very poor. Consequently, prophylaxis was thought to be a critical factor. Based on the background of MRSA infections, 1) careful selection and total dosage of antibiotics, 2) repeated sterilization of surgical wound including insertion site of IVH route. 3) follow up of the patients with MRSA isolation, should be carefully considered to prevent MRSA infections.

View full abstract

We performed a multicenter clinical trial of cefuzonam (CZON) to evaluate its efficacy and safety in 21 patients over 65 years old with biliary tract infections. CZON was intravenously administered (2-4 g/day) to 11 patients with acute cholecystitis, 8 patients with acute cholangitis and 2 patients with acute cholecystitis plus cholangitis. Seven patients were concurrently treated by biliary drainage. The following results were obtained.
1) The overall clinical efficacy rate was 100%.
2) Bacteriological efficacy was assessed in 4 patients. Bacterial eradication was observed in 3 patients, and bacterial decrease was seen in 1 patient.
3) The clinical adverse effect, skin eruption, which was observed in only 1 patient (5%), was mild and transient.
4) The clinical usefulness rate was 100%.
5) The concentration of CZON in the bile 1 hour after intravenous injection of 1 g of the drug was very favorable, 588. 8 ± 276. 9 μ g/ml (mean in 5 patients). The serum concentration of CZON 1 hour after intravenous injection of 1 g of the drug was 64.7 ± 16.3 μ g/ml.
We conclude that CZON is very effective and safe in patients over 65 years old with biliary tract infections.

View full abstract

The in vitro activity of imipenem (IPM) in combination with amikacin (AMK), gentamicin (GM) or ciprofloxacin (CPFX) against Pseudomonas aeruginosa and Staphylococcus aureus (MRSA) was studied. A multicenter clinical trial using imipenem/cilastatin sodium (IPM/CS), with or without AMK for respiratory tract infections was also performed, The following results were obtained
1) The mean FIC indicesof the IPM/AMK combination against 12 strains of clinically isolated IPM-resistant P. aeruginosa were 0.16 (range: 0.06-0.25), IPM/GM 0.17 (0.09-0.25), and IPM/CPFX 0.12 (0.09-0.19). The mean FIC indices of the IPM/AMK combination against 12 strains of clinically isolated MRSA were 0.10 (0.06-0.19), IPM/GM 0.13 (0.09-0.19) and IPM/CPFX 0.13 (0.06-0.25). IPM combined with AMK, GM or CPFX showed synergistic effects.
2) Thirty five patients with respiratory tract infections were treated with IPM/CS alone and/or IPM/CS plus AMK. IPM/CS alone was administered to 10 patients (5 with pneumonia, 2 with chronic bronchitis, 2 with bronchiectasis and 1 with aspiration pneumonia). IPM/CS plus AMK were administered to 25patients (8 with pneumonia, 5 with chronic bronchitis, 5 with bronchiectasis, 3with diffuse panbronchiolitis, 2 with aspiration pneumonia and 2 with empyema).
3) The clinical efficacy of IPM/CS monotherapy was excellent in 5, good in 2, fair in 1 and poor in 2, the overall efficacy rate being 70%. That of IPM/CS plus AMK combination therapy was excellent in 15 and good in 10, the overall efficacy rate being 100%.
4) Bacteriologically, 9 of 13 strains were eradicated (69.2%), one was decreased 3 persisted and there were 5 superinfections with IPM/CSmonotherapy. Fifteen of 22 strains were eradicated (68.2%), 3 decreased, 4 persisted and there were 2 superinfections with IPM/CS plus AMK combination therapy.
5) No side effects were observed. Laboratory findings revealed mild and transient eosinophilia in one case receiving combination therapy. The safety of IPM/CS monotherapy and IPM/CS plus AMK combination therapy was good.
These resultssuggest that while IPM/CS is useful for respiratory tract infections, IPM/CS plus AMK combination therapy is more effective, . especially for infections with P. aeruginosa and/or MRSA infections.

View full abstract

The efficacy of mupirocin nasal ointment in eliminating nasal carriage of Staphylococcus aureus, including MRSA, and preventing recolonization was assessed together with its safety and usefulness. Mupirocin nasal ointment was applied to all patients admitted to certain selected wards for three days to assess elimination of and colonization with S. aureus, including MRSA. Hospital staff members working in these wards who were nasal carriers of S. aureus were also treated with mupirocin nasal ointment. The safety and usefulness of this preparation were also evaluated, and the results are as follows:
1. On the day after and one week after the final application, mupirocin nasal ointment had eliminated S. aureus from 100% of the 15 hospital staff members found to be nasal carriers. Six patients were found to be nasal carriers of S. aureus, and it had been eliminated from 5 of them by the day after the final application and from all of them one week later.
2. Eight patients who were not nasal carriers of S. aureus were treated with mupirocin nasal ointment. None of them were colonized with S. aureus on the day after, or one week after the final application.
3. Neither adverse effects nor adventitious symptoms were reported by any of the subjects enrolled in this investigation. The test preparation was assessed as “safe” in all 37 case
4. The usefulness of mupirocin nasal ointment in eliminating S. aureus was assessed as “extremely usefu” in all 15 hospital staff members. In 5 of the 6 patients, it was assessed as “extremely useful” and in the remaining patient, it was assessed as “useful”.
5. Mupirocin nasal ointment was assessed as “extremely useful” in preventing colonization with S. aureus in all 8 patients.

View full abstract