We investigated the in vitro and in vivo antibacterial activities of teicoplanin (TEIC) and compared them with those of vancomycin, erythromycin (EM), ampicillin (ABPC), ofloxacin, and gentamicin. The antibacterial spectrum of TEIC is restricted to gram-positive bacteria. Results of studies of the antibacterial activity of TEIC against gram-positive bacteria isolated from 1985 to 1987 showed that TEIC is highly active against staphylococci, streptococci, and enterococci, including methicillin-resistant staphylococci and multi-resistant enterococci. A time-kill study showed potent bactericidal activity of TEIC against Staphylococcus epidermidis, Streptococcus pyogenes, and Streptococcus pneumoniae. The in vivo antibacterial activity of TEIC against experimental infections in mice was greater than those of EM and ABPC.

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The MIC₉₀ of teicoplanin (TEIC) against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), coagulase-negative staphylococci, Streptococcus pyogenes, Streptococcus pneumoniae, β-strepotococci, Enterococcus faecalis, Enterococcus faecium, and ampicillin-resistant Haemophilus influenzae were 1.56, 1.56, 6.25, 0.39, 0.39, 0.39, 0.78, 1.56, and 100μg/ml, respectively, employing 14-52 clinical isolates.
The bactericidal activity of TEIC against highly resistant MRSA was much greater than that of the other antibiotics tested.
Synergy of the bactericidal effect between TEIC and serum complement against S. aureus 209 P was not prominent, although S. aureus cells were phagocytized and digested by mouse cultured macrophages in the. presence of higher than 1/4 MIC of TEIC.
The cytostatic activity of TEIC against mammalian cells was much weaker than that of the other antibiotics. The growth of CHO-K 1, HeLa, and IMR-32 cells was not affected even in the presence of 100μg/ml of TEIC. This antibiotic possesses an apparently selective toxicity.
Synergy of the bactericidal effect of TEIC and cefinetazole against MRSA strains was prominent.

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The in vitro and in vivo antibacterial activities of teicoplanin (TEIC) were compared with those of vancomycin (VCM), ampicillin (ABPC), cefazolin (CEZ), gentamicin (GM) and erythromycin (EM).
TEIC had a narrow antibacterial spectrum, and the antibacterial activity of TEIC against gram-positive organisms, such as Staphylococcus spp., Streptococcus pneumoniae, and Enterococcus faecalis was superior to that of CEZ and VCM, and almost the same as that of ABPC and EM. Its activity against methicillin-resistant Staphylococcus aureus (MRSA) was especially potent.
In experimental systemic infection in mice, the therapeutic effects of TEIC on infections due to S. aureus TMS 288 (MRSA), E. faecalis No.3, and S. pneumoniae TMS 3 were superior to those of ABPC, CEZ, GM, EM, and VCM. TEIC was well absorbed and showed high levels in mouse serum following subcutaneous administration.

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The antimicrobial activity of teicoplanin (TEIC) against gram-positive cocci obtained from various clinical specimens was tested and compared with those of vancomycin (VCM), imipenem (IPM), minocycline (MINO), arbekacin (ABK) and lomefloxacin (LFLX). The MIC₉₀ of TEIC against enterococcal species was the lowest among those of other drugs tested (two to three dilutions lower than that of VCM). In streptococcal species, the MIC₉₀ of TEIC was 0.2 μg/ml. This value was the second lowest among the drugs tested (IPM was the lowest: MIC₉₀, ≤0.05 μg/ml). The antimicrobial activity of TEIC against methicillin-resistant Staphylococcus aureus (MRSA) was almost the same as that of VCM, and was superior to that of other drugs. Against methicillinsensitive S. aureus, although IPM had the greatest activity, the activity of TEIC was the same as that of VCM, MINO and ABK.
Using an in vitro pharmacokinetic system, the antimicrobial activity of TEIC (0.2g, one dose per day) against MRSA was demonstrated to be superior to that of VCM (1g, one dose per day) and the same as that of the drug (1g, two doses per day).

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The antibacterial activity of teicoplanin (TEIC) was determined against gram-positive bacteria clinically isolated in phase II study, from June 1990 to July 1991, and phase III study, from July 1991 to October 1992. The in vitro antibacterial activities of TEIC and vancomycin (VCM) in combinations with β-lactams were studied against methicillin-resistant Staphylococ-cus aureus (MRSA) and Pseudomonas aeruginosa. The results obtained are summarized as fol-lows:
1) Of 107 strains of S. aureus, 16.8% were methicillin-susceptible S. aureus (MSSA) and 83.2% MRSA. The MIC₅₀ and MIC₉₀ of TEIC against S. aureus, including MRSA, Coagulase-negative staphylococci (CNS), and Streptococcus spp. were similar to those of VCM, and the MIC₅₀ and MIC₉₀ of TEIC against Enterococcus spp. were lower than those of VCM by 2 tubes-fold (4 times). TEIC was significantly superior to VCM in light of the MIC range against S. aureus (p<0.01, x²-test), CNS (p<0.01, ²-test), and Enterococcus spp.(p<0.01, x²-test).
2) The in vitro antibacterial effects of combinations of TEIC with cefotiam (CTM), flomo-xef (FMOX) and imipenem (IPM) against MRSA (methicillin MIC≥128μg/ml) reached 80%, with a FIC-index ≤0.5 and were superior to those of VCM with CTM, FMOX and IPM. These results were due to the strong synergistic activities of the combination of TEIC and β-lactam at a sub-MIC concentration of TEIC.
The combined activities of TEIC with IPM, ceftazidime (CAZ), cefsulodin (CFS), and aztreonam (AZT) against P. aeruginosa did not show a FIC-index > 2 in any combination. These results indicated that TEIC did not have any antagonistic activity in combination with β-lactams against gram-negative rods.

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The antimicrobial activity of the new glycopeptide antibiotic, teicoplanin (TEIC), was deter-mined against 290 recent clinical isolates of gram-positive bacteria, including streptococci, enterococci, staphylococci, and Clostridium difficile. TEIC showed superior antimicrobial activity against the strains tested, in comparison with vancomycin, ampicillin, piperacillin, cefazolin, cefmetazole, cefotaxime, cefoperazone, and sulbactam-cefoperazone. No strain was resistant to TEIC. The MIC₉₀ of TEIC against streptococci and enterococci were less than 0.2 and 0.78 pg/ml, respectively. Strains of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) were inhibited by 1.56 and 3.13μg/ml of TEIC, respectively. Resistance to TEIC was induced in stepwise fashion in broth cultures of Streptococcus pneumoniae, Enterococcus faecalis, S. aureus or MRSA strains, but the rate was very slow and the increased level of the resistance was not exceed fourfold.

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Teicoplanin (TEIC) is structually related to vancomycin and possesses a similar spectrum of in vitro antibacterial activity. Most gram-positive organisms are susceptible to TEIC. Staphylococci, including methicillin-resistant Staphylococcus aureus (MRSA), are susceptible to TEIC, while some of the coagulase-negative staphylococci (CNS), including Staphylococcus epidermidis, are slightly less susceptible.
Bacterial resistance to non-glycopeptide antibacterial drugs has no influence on the activity. Inoculum size in liquid media has a minor influence on the in vitro activity of TEIC, but decreases the MIC in heavy inoculum size by the agar plate dilution method. TEIC shows strong growth inhibition against a strain of S. aureus with a long generation time.
Synergy, as determined by the checker-board doubling dilution techniques, and defined as a 2-fold reduction in the MIC for both drugs or fractional inhibitory concentration (FIC) of < 1.0, was observed against S. aureus, including MRSA, CNS, and Enterococcus faecalis for TEIC with β-lactam antibiotics, such as imipenem, cefoperazone, and piperacillin. Antagonism, defined as a 4-fold increase in the MIC for both drugs or an FIC of > 2, was not found for TEIC in combination with β-lactam antibiotics. Synergy was also found for TEIC in combination with lysozyme by the paper strip method.

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The in vitro activity of teicoplanin (TEIC), a new glycopeptide, was studied in a variety of anaerobic bacteria. TEIC was more active than vancomycin (VCM) against gram-positive cocci including Peptostreptococcus spp., Clostridium spp., and Gardnerella vaginalis, a fastidious facultative anaerobe, and comparable to VCM against Mobiluncus spp. Among gram-negative rods, although TEIC had little activity against Bacteroides spp. including Bacteroides fragilis group organisms, this compound was active against Prevotella spp. that were not susceptible to VCM. In addition, TEIC was more active than VCM against Porphyromonas spp. TEIC had little activity against Lactobacillus spp., of a major member of the intestinal flora, as did VCM.

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We compared the in vitro and in vivo antibacterial activities of teicoplanin (TEIC) with those of ampicillin (ABPC), cefotiam (CTM), minocycline (MINO), and vancomycin (VCM), and obtained the following results.
TEIC had an antimicrobial spectrum against gram-positive and anaerobic bacteria, but did not have antibacterial activity against gram-negative bacteria. The antibacterial activity of TEIC against Staphylococcus aureus was slightly inferior to that of ABPC and superior to those of CTM, MINO, and VCM. Against Enterococcus faecalis, TEIC was the most potent compound of all the antimicrobial agents tested. On the other hand, in the sensitivity distribution of clinically isolated strains, its activity against S. aureus, methicillin-resistant S. aureus (MRSA), and Staphylococcus epidermidis was slightly inferior to that of VCM and superior to that of MINO.
The activity of TEIC against S. aureus, MRSA, S. epidermidis, and E. faecalis was largely unaffected by the type of culture medium, the addition of horse serum, inoculum size and the pH of the medium.
TEIC showed bacteriostatic action against S. aureus and E. faecalis and bactericidal action against MRSA and S. epidermidis.
In the morphological examination by phase-contrast and transmission electron microscopy, TEIC produced swelling and lysis of S. aureus and E. faecalis cells. It was found that the lytic site of these cells observed after treatment with TEIC was in the sites of septum formation.
The therapeutic efficacy of TEIC in intraperitoneal infections in mice was comparable to that of CTM and superior to those of VCM and MINO against S. aureus. In MRSA infection in mice, TEIC demonstrated therapeutic efficacy slightly inferior to those of VCM and MINO but showed the highest therapeutic activity against Streptococcus pneumoniae and Streptococcus pyogenes among the drugs tested.
Against subcutaneous abscess infections experimentally induced by S. aureus in mice, the therapeutic efficacy of TEIC was superior to that of VCM.

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We examined the method to analyze teicoplanin (TEIC) concentration in biological samples by both bioassay and high performance liquid chromatography (HPLC).
Bioassay by the agar well method used Bacillus subtilis ATCC 6633 as the test microorganism. TEIC was analyzed in plasma with more than 2 times dilution with horse serum and in urine with more than 5 times dilution with Tris-HCl buffer, pH 7.4, containing 2%(v/v) horse serum. The lower limits of quantification (LLQ) in plasma and urine were 0.6μ/ml and 1.0μg/ml, respectively. Both samples could be analyzed within an error of 10% and less than a 5% coefficient of variation. TEIC in feces had 2.5μg/g wet weight as LLQ when the fecal extract with alkaline (pH 10) was analyzed after washing with water (pH 6.5) followed by acetone.
Six major components were analyzed by HPLC (gradient elution method) using solid phase extraction with Sep-Pak^TM CN. LLQs in plasma and urine were about 5μg/ml and 15μg/ml as total TEIC, respectively.
Our bioassay and HPLC methods were shown to have a close correlation.

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In order to investigate the safety and pharmacokinetics of teicoplanin (TEIC), three studies were performed in healthy volunteers. In all studies, the drug was given intravenously for 30 min.
Study 1: Single doses of 2, 4 and 8mg/kg and a multiple dose of 4mg/kg for 7 days were administered to 5 subjects in each dose group. No abnormal findings were observed except in one subject in the multiple dose group who showed slight increases in GOT, GPT, and γ-GTP. The peak plasma concentrations after single doses were dose related. The elimination half-lives were 46.08 to 56.88 h. Within 96 h, 45.6 to 54.0% of the drug was excreted into urine. Fecal excretion was extremely small. After multiple dosing, the plasma trough level gradually increased, reaching an almost steady state after 5 or 6 doses. Pharmacokinetic parameters were similar in the single and multiple dose studies.
Study 2: To 3 subjects, a dose of 400mg was given twice a day on the 1st day, then once a day for 4 days. No abnormal events were observed throughout the treatment period. However, 7 days after completion one subject showed swelling of tonsil, cough, and fever followed by slight increases in GOT, GPT, and LDH. The plasma trough level rapidly increased after a loading dose and was maintained at 10.3 to 12.2 μg/ml thereafter.
Study 3: A single dose of 400 mg was given to 6 subjects. No changes in plasma histamine concentration were observed except for a slight non-drug-related increase in one subject. It was considered that TEIC does not affect histamine release.

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The effect of 7-day administration of teicoplanin (TEIC), a novel glycopeptide, on human fecal flora was studied. Intravenous drip infusion at a dose of 4mg/kg of TEIC was given once a day to 5 healthy adult males. One of the 5 cases was excluded from the evaluation because TEIC was given for only 5 days (abnormal laboratory findings for liver function were recorded on day 5). Little change in anaerobic and aerobic fecal flora were observed on the genus and group level; most changes in the bacterial number were 2 log or less. Species of the Bacteroides fragilis group, Enterobacteriaceae and Enterococcus spp. were changed little by the administration of TEIC. No differences in susceptibility to TEIC were noted in fecal strains isolated before, during, and after TEIC administration. These results suggest that TEIC had little effect on human intestinal flora.

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We determined the blood level of teicoplanin (TEIC) in 64 patients with infectious diseases 15 with infectious endocarditis, 15 with septicemia, 15 with pneumonia, 19 with skin and soft tissue infections, and 10 with myelitis/arthritis) in trials conducted with a view to investigating its clinical dosage levels.
Daily maintenance doses of 200mg and 400mg of TEIC showed trough levels (mean steady state) of approx. 5μg/ml and approx. 10μg/ml, respectively. Loading doses, which were given on day 1, accelerated the onset of the target mean steady state of daily maintenance doses of the drug. The clinical effects of TEIC in 133 patients were analyzed and evaluated in clinical dosage investigation trials and general clinical studies. More effects were observed with 400mg (daily maintenance doses) than with 200mg (daily maintenance doses). Also, loading doses caused higher efficacies. The drug was markedly effective against MRSA infections (infections caused by methicillin-resistant Staphylococcus aureus)
The results of our studies indicate that TEIC attained its target blood levels more rapidly with the administration of loading doses than without them and that the loading doses enhanced the efficacy of TEIC. The results also suggested that TEIC has postantibiotic effects on gram-positive organisms and that it can demonstrate such effects on a “once daily” regimen of administration.

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The clinical effects of teicoplanin (TEIC) on septicemia, infective endocarditis and respiratory tract infections were evaluated in 40 medical institutes. Reported herein are the results of the evaluations.
Dose-finding studies of TEIC were carried out in patients with septicemia, infective endocarditis or pneumonia caused by gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA), and plasma concentrations in those patients were investigated in the studies. In patients with septicemia or infective endocarditis, 400mg/400mg → 400mg/day of TEIC showed high trough levels in blood soon after administration and proved effective in many of the patients so treated. The effect was found to be correlated with the level in plasma. In patients with pneumonia, 400mg/400mg→400mg/day of the drug exhibited high trough levels in blood, which, however, showed no clear correlation with clinical effects.
Open clinical trials were conducted at 400mg/400mg→400mg/day of TEIC in patients with septicemia/infective endocarditis and 200mg/200mg→200mg/day and 400mg/400mg→400mg/day of TEIC in patients with respiratory tract infections. The dose of 400mg/400mg→400mg/day was effective in 75.0 %(6 of 8 patients) of the patients with septicemia/infective endocarditis and 82.4%(14 of 17 patients) of the patients with respiratory tract infections. The dose of 200mg/200mg→200mg/day was effective in 81.8%(9 of 11 patients) of the patients with respiratory tract infections. Bacteriologically, 19 of 23 strains (82.6%) were eradicated with TEIC. MRSA responded to TEIC, with 6 of the 8 strains (75.0%) treated with the drug eradicated.
The incidence of side effects was only 4.4%(5 of 113 patients). Clinical laboratory findings indicated transient episodes of liver dysfunction, but they were not severe.
It can be concluded that TEIC is clinically useful and safe in the treatment, of infections caused by gram-positive organisms, including MRSA.

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The efficacy of teicoplanin (TEIC), a new glycopeptide antibiotic agent, was evaluated in an open trial under limited conditions, which were of the patient and the diagnosis, at 3 hospitals in Kanagawa prefecture. Respiratory infections, regarded as caused by Staphylococcus aureus, were treated by either 200mg twice on the first day followed by the same dose once a day (group 1) or 400mg twice on the first day followed by the same dose once a day (group 2) for 1-3 weeks.
Four patients, two with pneumonia and two with chronic bronchitis episodes, group 1, and four patients, two with pneumonia, one diffuse bronchitis and one sequential bronchitis episodes, group 2, were treated with TEIC. Three patients in group 1 and all in group 2 were assessable for efficacy and all eight cases were evaluable for safety.
Two of the three patients in group 1 and three of the four in group 2 showed good clinical results. One patient in each group had methicillin-resistant S. aureus as the causative organism. Clinical efficacy was fair in the patient in group 1 and superinfection was noted. The patient in group 2 showed good results clinically and eradication of the causative organism.
No severe adverse reaction occurred, but eosinophilia was seen in a patient in group 1.
The plasma concentration of TEIC was determined by bioassay. According to comparison of the trough points between 2 doses, which were from 24 hours after the first dose to the seventh day, the plasma levels of group 2 cases were 2-4 times higher than those of group 1 cases. When both groups reached the steady state at and after 1 week, the level was 5-10μg/ml, which is regarded as the range of the therapeutic plasma concentration of TEIC.
On the basis of the results, we suggest that both groups 1 and 2 might be recommended as the dosages of TEIC for respiratory infectious diseases.

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After preliminary observations on the relationships of dose with the efficacy andsafety of a new glycopeptide antibiotic, teicoplanin (TEIC), in patients with skin and soft tissue infection at maintenance doses of 200 to 400mg, a comprehensive clinical dose-finding studywas performed and blood concentrations were assayed after each dose as well. Thereafter, in order to collect more clinical results, an open clinical study evaluating the efficacy and safety of the drug was performed.
1) The clinical efficacy rates by dose in the clinical-dose finding study were as follows: group A: 200mg/day (once a day), 4/7; group B: 400mg/day on the 1 st day (once a day), followed by 200 mg/day, 3/5; group C: 400mg/day (divided into 2) on the 1 st day, followed by 400mg/day (once a day), 2/2; group D: 400 mg/day (once a day), 2/2; and group E: 800mg/day (divided into 2) on the 1 st day, followed by 400mg/day (once a day), 3/4. Further, from the course of the blood concentration in groups C and E, a loading dose effect with a high bacteriological response was observed. No serious adverse reactions or abnormal clinical laboratory findings were observed, and at maintenance doses of 200 and 400mg, no dose-dependent trends in the occurrence of side effects were observed.
2) In the open clinical study, 29 cases of gram-positive infection were collected, 27 of which were evaluated for efficacy. Two dosage groups, 200mg/200mg→200mg/day and 400mg/400mg→400mg/day, were examined, and the clinical efficacy rate was 11/11 (100%) in superficial prulent infection, 11/13 (84.6%) in superficial secondary infection, and 100% in 13 cases of methicillin-resistant Staphylococcus aureus (MRSA) infection. The bacteriological elimination rate was 84.2% in all cases, and 100% in MRSA infection (12 cases).
Thus, it was considered that TEIC is a highly useful drug for the treatment of skin and soft tissue infection.

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We carried out a multicenter collaborative trial at 11 institutes to evaluate the clinical efficacy of teicoplanin (TEIC), a newly developed glycopeptide injectable antibiotic, in the treatment of bone and joint infections. For the treatment of osteomyelitis and arthritis, TEIC was administrated for 14 days, as a rule, at dosage 1 (400mg every 12hr. on the initial day, followed by 400mg daily) or dosage 2 (400mg daily).
A total of 39 patients were enrolled in the trial, and the number of evaluable cases was 36. The efficacy rates for osteomyelitis and arthritis were 73.5% and 50.0%, respectively.
The efficacy rates classified by dosage were 66.7% with dosage 1, 73.7% with dosage 2 and 100% with other dose regimens. The bacteriological response was evaluated in 23 cases and showed an eradication rate of 87.0%. Based on the above results, we concluded that TEIC is a useful antibacterial agent for the treatment of bone and joint infections.

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Data on the side effects and abnormal clinical laboratory findings of teicoplanin (TEIC) were reviewed. Of the 218 cases treated with TEIC, 10 (4.6%) reported side effects: fever in 4 cases, skin rash in 3, and palpitation and hypotension, anorexia and jaundice in one case each. All of the side effects were moderate in severity, and 9 patients were withdrawn from the therapy.
No difference in frequency was observed between the dosage of 200 mg/day and that of 400 mg/day. Of 215 cases evaluated, 46 (21.4%) reported abnormal variations in clinical laboratory findings. The most common episodes were increases in GOT/GPT and eosinophilia. The incidence of renal disorders was low. Red man syndrome and auditory disorders were not reported. Histamine release, as noted with vancomycin, was not observed with TEIC.

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We investigated teicoplanin (TEIC), a glycopeptide antibiotic, for its antimicrobial activities against Staphylococcus aureus and clinical effect. The MICs of TEIC were determined against 156 strains of methicillin-sensitive S. aureus (MSSA) and 56 strains of methicillin-resistant S. aureus (MRSA), which were isolated clinically in 1988-1989, and 79 strains of MRSA isolated in 1990-1991. The MIC₉₀ were 0.78, 1.56 and 3.13μg/ml, respectively. Teicoplaninresistant strains were not obtained. The activity of TEIC was superior to those of reference penicillins and cephems, and similar to that of vancomycin. The clinical efficacy of TEIC was evaluated in 3 patients with pneumonia. The isolated organisms were MRSA, MSSA and Streptococcus pneumoniae in one case each. One patient received a dosage of 200 mg daily, and two patients received 200 mg every 12 hours on the initial day, followed by 200 mg daily. The period of administration was 14 to 15 days. The clinical efficacy was excellent in one case and good in 2 cases, and causative organisms were eradicated in all cases. No side effects or abnormal laboratory findings were observed.

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We measured in vitro antimicrobial activities of teicoplanin (TEIC), a new parenteral glycopeptide antibiotic, and evaluated its therapeutic efficacy in respiratory tract infections caused by gram-positive cocci. The minimum inhibitory concentrations (MICs) of TEIC, vancomycin (VCM), ampicillin, ceftazidime and imipenem against a total of 132 strains consisting of 7 different species, methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens and Pseudomonas aeruginosa, were determined by the micro-broth dilution method using the Dynatech MIC 2000 system. As shown by MICs, TEIC was the most active against MSSA and MRSA. Against Enterobacteriaceae and P. aeruginosa, TEIC was ineffective, like VCM. A dose of 200 mg (4 cases) or 400 mg (2 cases) of TEIC was given daily to 6 patients for 8 to 19 days (mean: 13.8 days): three with acute pneumonia, two with secondary infection in association with old pulmonary tuberculosis and one with secondary infection in association with lung cancer. The clinical effects were excellent in three, good in two and fair in one (efficacy rate: 83.3%). Six strains were identified as causative organisms: four strains of Streptococcus pneumoniae, and one strain each of MRSA and anaerobic Streptococcus constellatus. All of them were eradicated by an administration of TEIC. Transient elevation of alkaline-phosphatase was observed in one patient, but it disappeared after the completion of therapy. From the above results, we conclude that TEIC is a useful antibiotic for parenteral use in the treatment of respiratory tract infections caused by gram-positive cocci, especially MRSA.

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The postantibiotic effects (PAE) and clinical efficacy of teicoplanin (TEIC) were investigated. The following PAE were observed when methicillin-sensitive Staphylococcus aureus 209 Pstrain was exposed to TEIC and vancomycin (VCM) for 1 hour and 2 hours; 5.1h and 14.6h with 2 MIC of TEIC, 2.7h and 3.5 h with 2 MIC of VCM, 13.2h and 17.4h with 4 MIC of TEIC and 3.0h and 3.3h with 4 MIC of VCM. The PAE of the agents on methicillinresistant S. aureus (MRSA) TK 784 P strain were as follows (1 hour and 2 hours): 15.5h and 18.7h with 2 MIC of TEIC, 1.6h and 2.2h with 2 MIC of VCM, >24h and >24h with 4 MIC of TEIC, and 1.4h and 1.9h with 4 MIC of VCM.
Clinically, 3 of 7 strains of MRSA and 1 strain of Streptococcus sanguis II were eliminated with TEIC. Of the patients treated with TEIC, 3 were evaluated as good, 3 as fair, 2 as poor, and 1 as not-evaluable. No side effects were observed. One patient showed a slight increase in creatinine on clinical laboratory tests.

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Investigations were conducted on the antibacterial activities, sub-MIC effects, plasma concentrations and clinical response of teicoplanin (TEIC), a new injectable glycopeptide antibiotic, and the results were as follows:
1) Antibacterial activities
The range of MICs of TEIC on methicillin-resistant Staphylococcus aureus (MRSA) were 0.2 to 1.56 μg/ml, almost equal to those of arbekacin (ABK) and one tube-fold superior to those of vancomycin (VCM).
2) Sub-MIC Effects
The bactericidal activities of antibiotics on those organisms of MRSA treated with a MIC (each of the antibiotics mentioned) equivalent to 1/4 of human polymorphonuclear leukocytes in healthy adults were augmented in groups given gentamicin (GM) and TEIC while showing tendencies of diminution in groups given ofloxacin (OFLX), minocycline (MINO), methicillin (DMPPC), cefazolin (CEZ), cefmetazole (CMZ) and VCM.
3) Plasma concentrations
The mean peak plasma concentrations of TEIC at the initial doses of 200 mg and 400 mg with intravenous dripping were 23.89 μg/ml and 45.1 μg/ml, respectively, and at the initial doses of 200 mg and 400 mg were 1.66μg/ml and 3.88μg/ml, respectively, 12 hours post administration.
4) Clincal results
A total of 8 patients participated in the clinical study. The infections treated included pneumonia (7 patients) and septicemia (1 patient), including MRSA infections (3 patients). TEIC proved effective in 3 of the patients treated.
None of the patients showed any side effects clinically, and none showed abnormal findings in clincal laboratory tests. The results above suggest that TEIC will be usable and useful on a regimen of intravenous dripping in the treatment of infections caused by MRSA.

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We investigated the antimicrobial activities of teicoplanin (TEIC) against clinically isolated gram-positive bacteria and compared them with those of vancomycin (VCM), ampicillin (ABPC) and piperacillin (PIPC). We administered TEIC to 2 patients with pneumonia and one with infectious endocarditis, and its clinical efficacy and safety were evaluated.
The antimicrobial activity of TEIC against Staphylococcus aureus (both methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA)) was slightly superior to that of VCM, with a MIC distribution of 0.12-1μg/ml. Some strains of Staphylococcus epidermidis needed MICs higher than 4μg/ml, but MIC₅₀ and MIC₉₀ were 0.5 and 4μg/ml, respectively. MICs against Enterococcus faecalis were significantly superior to those of VCM.
The clinical efficacy of TEIC at a daily dose of 200 mg given by intravenous infusion for a case of pneumonia caused by MSSA was poor, and it was fair for a case of pneumonia caused by MRSA.
In a case of infectious endocarditis, the efficacy of TEIC at a daily dose of 400 mg for 11 days was not satisfactory, and it was evaluated as fair.
Skin rash with slight eosinophilia was observed in a case of pneumonia, but no other side effects or abnormal findings were observed in laboratory examinations conducted after the treatment.
According to the above results and its pharmacokinetic character, TEIC is considered to be an interesting drug for the control of gram-positive bacterial infection, but more clinical studies including combination chemotherapy with other drugs are needed to make the final evaluation.

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A newly developed glycopeptide antibiotic, teicoplanin (TEIC), was evaluated in vitro and in vivo in comparison with imipenem, ceftazidime, ceftizoxime, cefuzonam, piperacillin, KT-3777, cefaclor, cefixime, amoxicillin, vancomycin, cefotiam and minocycline. The results were as follows,
1) Antimicrobial activity: Minimum inhibitory concentrations (MICs) against 180 clinical isolates including 5 different species were determined by the microbroth dilution method. TEIC showed excellent antimicrobial activity against gram-positive bacteria including methicillinresistant Staphylococcus aureus (MRSA).
2) Clinical efficacy and adverse reactions: 8 patients with infections such as sepsis, pneumonia and pulmonary abscess were treated with TEIC, and the overall efficacy was good in 3 cases, poor in 1 case and unjudged in 4 cases. Fever was observed in 1 case as a side effect of TEIC. Eosinophilia in 1 case and elevation of GOT and GPT in 1 case were also observed as abnormal laboratory findings, however, they were mild and transient, and improved rapidly after the completion of TEIC treatment.

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We evaluated in vitro activities and pharmacokinetics of teicoplanin (TEIC), a new glycope-ptide antibiotic, and its clinical efficacy in 4 patients with gram-positive bacterial infections. The MIC₉₀ against Streptococcus pneumoniae (32 strains), Streptococcus pyogenes (15 strains), Streptococcus agalactiae (8 strains), Enterococcus faecalis (30 strains) and α-streptococci (25 strains) were 0.2μg/ml, 0.78μg/ml, 0.39μg/ml, 1.56μg/ml and 0.39μg/ml, respectively. The MIC₉₀ against Haemophilus influenzae (45 strains) and Branhamella catarrhalis (37 strains) were>100μg/ml and 25μg/ml, respectively. The MIC₉₀ against methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) were 0.78μg/ml and 0.78μg/ml in period I (April 1982-March 1983, MSSA 50 strains and MRSA 29 strains). The MIC₉₀ against MSSA and MRSA were 0.39μg/ml and 0.39μg/ml in period II (January 1988 March 1988, MSSA 29 strains and MRSA 33 strains), 0.78μg/ml and 1.56μg/ml in period III (October 1990 November 1991, MSSA 39 strains and MRSA 40 strains). The two strains of S. aureus highly resistant to vancomycin (VCM, MIC>100μg/ml) were observed in the urine of a patient with complicated urinary tract infection and iter of a patient with bed sore infection in period II, but were sensitive to TEIC (0.2μg/ml and 0.39μg/ml). The in vitro activity of TEIC against those bacteria was superior to that of VCM.
The serum level of TEIC was studied in an 82 year-old womam with pyothorax caused by MRSA. The maximum serum level was 60.4μg/ml after intravenous administration of 200mg/ml. At three hours after intravenous administration, 18.3 μg/ml of TEIC was detected.
Four patient with sepsis caused by Enterococcus faecium, sepsis caused by S. aureus and Clostridium spp., pyothorax caused by MRSA and carbuncle caused by MRSA were studied for the clinical evaluation of TEIC. TEIC was given intravenously at 200-400 mg per day for 5-14 days. The rate of clinical efficacy was 100%, and all the causative organisms were eliminated. No adverse effect was observed.
We concluded that TEIC is a very useful intravenous antimicrobial agent for the treatment of gram-positive infections, including MRSA infections.

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We performed basic and clinical studies on teicoplanin (TEIC), a new glycopeptide antibiotic, and the following results were obtained.
1. Antimicrobial activity
The minimum inhibitory concentrations (MIC) of TEIC against a total of 432 clinically isolated strains of 6 species were measured and compared with those of vancomycin, minocycline, erythromycin, clindamycin, ofloxacin, imipenem, rifampicin (RFP), clarythromycin and tosufloxacin, using the MIC-2000 System (Dynatech Laboratories).
The MIC₉₀ of TEIC was 0.78μg/ml against methicillin-resistant Staphylococcus aureus (MRSA), and TEIC showed stronger bactericidal activity than other antibiotics except RFP.
TEIC showed much activity than other antibiotics against other gram-positive bacteria.
2. Clinical study results
TEIC was given five patients (3 cases of pneumonia, one of pleuritis and one of lung abscess) with respiratory infection. The clinical results were good in 3 and unknown in 2. No adverse reactions or abnormal laboratory findings were observed.
From the above results, we consider that TEIC to be a useful antibiotics for the treatment of MRSA and gram-positive bacteria in respiratory tract infections.

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1) The minimum inhibitory concentrations (MICs) (10⁶ cells/ml) of teicoplanin (TEIC), vancomycin (VCM), arbekacin (ABK) and methicillin (DMPPC) were determined against 24 strains of Staphylococcus aureus and 62 strains of coagulase-negative staphylococci (CNS) isolated from infectious skin lesions. The MIC50 of TEIC, VCM, ABK and DMPPC against S. aureus were 1.56, 1.56, 1.56 and 6.25μg/ml, respectively. The MIC₅₀ of TEIC, VCM, ABK and DMPPC against CNS were 1.56, 1.56, 0.78 and 6.25μg/ml, respectively.
2) TEIC (200 mg or 400 mg) was administered intravenously once a day for 3-22 days to patients with infectious skin diseases. The results were excellent in 3 cases and good in 3. One patient had appetite loss as a side effect. As to abnormal laboratory data, decreases in WBC and platelets were observed in one case.

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The minimum inhibitory concentrations (MICs) of teicoplanin (TEIC), vancomycin (VCM) and arbekacin (ABK) were determined by an agar dilution method for methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci.
Ninety percent minimum inhibitory concentrations (MIC₉₀) of TEIC, VCM, and ABK were 0.39, 0.39 and 1.56μg/ml against MRSA, respectively. TEIC was found to be as active as VCM against MRSA. In terms of MIC₉₀, TEIC (6.25μg/ml) was less active than VCM (1.56μg/ml) against Staphylococcus epidermidis, MICs of TEIC displayed a wider range than those of VCM in S. epidermidis, Staphylococcus haemolyticus and Staphylococcus hominis. TEIC was shown to be less active than VCM against these staphylococci.

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The comparative minimum inhibitory concentrations (MICs) of teicoplanin (TEIC) and vancomycin (VCM) for Staphylococcus aureus and Staphylococcus epidermidis were evaluated by a twofold agar dilution method. All 39 isolates of S. aureus and 25 of S. epidermidis strains were obtained from individual patients admitted to Keio University Hospital in 1988. TEIC was less active against both S. aureus and S. epidermidis than VCM. The MIC of TEIC for S. aureus ranged from 0.2 to 3.13μg/ml. Of these 39 strains, 25 strains were MRSA for which the MIC of methicillin (DMPPC) was more than 12.5 μg/ml. The MIC of TEIC for S. epidermidis ranged from 0.2 to 12.5 μg/ml. The MIC of DMPPC for these strains ranged from 0.39 to more than 100μg/ml.
An MRSA septicemia patient with aplastic anemia was successfully treated with 400 mg to 800 mg a day of TEIC. No side effects were observed. Although the MIC of DMPPC for this strain was determined four times, it was either 3.13 or 6.25μg/ml. However, the mecA gene of this strain was detected by the polymerase chain reaction method.

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Teicoplanin (TEIC), a new glycopeptide antibiotic agent, was evaluated in 6 infectious cases: 4 septicemia, 1 pneumonia and 1 decubitus infection caused by Staphylococcus aureus.
Methicillin-resistant S. aureus was the causative organism isolated in the 5 cases. Patients were given either 200 mg or 400 mg once or twice on the first day followed by the same dose once a day.
The clinical outcomes of the 2 cases evaluable as TEIC monotherapy were excellent and good. No adverse reactions occurred, but slight eosinophilia caused by TEIC was observed in a septicemia patient.

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We investigated the clinical efficacy and safety of teicoplanin (TEIC), a new glycopeptide antibiotic. TEIC was administered to 6 patients, 3 with septicemia and 3 with acute pneumonia, at a daily dose of 200-400 mg for 7-37 days.
The clinical efficacy was evaluated to be excellent in 1 patient with septicemia and good in the other 5 patients.
The bacteriological response was evaluated in 5 cases, and the causative pathogen was eradicated in 2 cases, decreased in 1, persisted in 1 and was replaced in 1.
Neither undesirable symptoms nor abnormal laboratory findings were observed during or after the administration of TEIC.

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A clinical study of teicoplanin was conducted in 5 patients who had been infected with methicillin-resistant Staphylococcus aureus (MRSA). Each of the patients received the drug at dosages of 0.2 or 0.4 g initially and 0.2 to 0.4g at intervals of 12 to 24 hours for 5 to 25 consecutive days thereafter. The results were as follows: Of the 5 patients treated, 1 was rated as “good”, 1 as “ & fair”, 2 as “poor” and 1 as “unevaluable.” Microbiologically, the organisms were eliminated in 1 patient and decreased in 1 patient. No change was observed in the remaining 3 patients. Aggravation of jaundice was observed as a side effect in 1 patient, whose clinical laboratory findings showed marked increases in total bilirubin, GOT and GPT. Slight increases in GOT and BUN were observed in one of the other 4 patients.

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We evaluated the clinical efficacy and safety of teicoplanin (TEIC), a new glycopeptide antibiotic. TEIC was administrated to 6 patients with bacteremia and one each with pneumonia and peritonitis. Seven patients received the drug intravenously, and one patient with peritonitis was treated with intraperitoneal TEIC. Clinical efficacy was good in 5 patients, fair in 1 and poor in 2. In terms of side effects, exanthema was observed in one, and in one patient, GOT, GPT and ALP were elevated after the administration of this drug.

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The clinical efficacy and safety of teicoplanin (TEIC), a new glycopeptide antibiotic, were studied in 2 patients with pneumonia, 1 with chronic bronchitis, 1 with septicemia, and 2 with subcutaneous abscess caused by methicillin-resistant Staphylococcus aureus (MRSA). MICs (10⁸ cells/ml) against 6 strains of MRSA were 0.78-3.13μg/ml, and serum trough levels of TEIC in 2 patients were about 4μg/ml. MRSA disappeared in 3, decreased in 1 and persisted in 2 patients, but the clinical efficacy was good in 1, fair in 1 and poor in 4 patients. The poorer than expected clinical efficacy, based on MIC and plasma levels, and bacteriological effects of TEIC were considered to be due to compromised conditions of the hosts such as the presence of cancer, surgical stress, age and malnutrition. There were no side effects, but slight and reversible elevation of eosinophils and serum transaminase were observed in 3 patients.

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The antimicrobial activity of teicoplanin (TEIC) was measured against clinically isolated strains of Staphylococcus aureus containing methicillin-resistant S. aureus (MRSA), coagulasenegative staphylococci (CNS), Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Enterococcus faecalis and Corynebacterium spp. The activity of the drug was compared with those of vancomycin (VCM), arbekacin (ABK), minocycline (MINO) and rifampicin (RFP) against Staphylococcus spp. The activities of cefazolin (CEZ) and ofloxacin (OFLX) were also measured against MRSA. Against S. aureus containing MRSA, TEIC showed almost the same activity as VCM, and no resistant strain was observed. Although RFP showed the most powerful activity among the drugs, some strains resisted it. ABK-, MINO-and OFLXresistant strains were found. Some strains of CNS resisted TEIC. The activity of TEIC was excellent against Streptococcus spp., E. faecalis and Corynebacterium spp.
TEIC was administered to two patients with staphylococcal septicemia, and clinical responses were good in one case and fair in the other. As to bacteriological efficacy, the isolate was eradicated in the case with the good result. No adverse reaction was observed in either case in spite of their severe underlying diseases.

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A comparison of the in vitro antimicrobial activity of teicoplanin (TEIC) with those of vancomycin (VCM), minocycline (MINO) and rifampicin (RFP) was performed in 295 clinical isolates from respiratory tract specimens including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive S. aureus (MSSA), Streptococcus pneumoniae, Enterococcus faecalis, Haemophilus influenzae and Moraxella subgenus Branhamella catarrhalis. The activity of TEIC was almost the same as that of RFP and superior to those of VCM and MINO against MRSA, MSSA, S. pneumoniae, and E. faecalis, and low against H. influenzae, M.(B) catarrhalis, similar to VCM. In one patient with infective endocarditis due to Streptococcus mitis, TEIC 200 mg was administered as a drip infusion once a day. This was clinically effective, but the patient had an adverse reaction with drug-induced fever from day 12 of treatment. The fever recovered immediately without specific treatment after discontinuation of the drug.

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Teicoplanin (TEIC), a new injectable glycopeptide antibiotic, was administrated to three patients suffering from methicillin-resistant Staphylococcus aureus (MRSA) pneumonia who were urider mechanical ventilation after cardiovascular surgery. Various clinical signs of pneumonia improved after the administration in all patients, including the disappearance or reduction of MRSA in sputum culture, reduction and/or purification of airway secretions and increase in PaO₂/FIO₂. Patients were weaned off mechanical ventilation, and the tracheal tube was extubated in two of them. No side effects were observed. Mild eosinophilia was observed in one patients. Slight thrombocytopenia and elevation of GOT, detected in one patient, were considered to be unrelated to the drug. We concluded that TEIC is efficacious for MRSA pneumonia after cardiovascular surgery.

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The in vitro antibacterial activity of teicoplanin (TEIC) was tested against Staphylococcus aureus isolated in the surgical field. MIC₅₀, MIC₉₀ and MIC range (μg/ml) of TEIC were 0.78, 1.56 and 0.39-4.56 respectively, against both methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). In comparison with 11 control drugs, the MIC₉₀ of TEIC was closest to that of minocycline against MSSA, and superior to any control drug against MRSA.

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Three patients with intractable surgical infections caused by methicillin-resistant Staphylococcus aureus (MRSA) were treated intravenously with teicoplanin. Two patients had mixed infections; Pseudomonas aeruginosa also was detected. They did not respond to teicoplanin. The third patient, with an infection of the wound of a leg amputation at the thigh level, did not respond, either, and MRSA was not eradicated. The first two patients had sufficient levels of teicoplanin in the blood. No side effects or abnormal changes in laboratory data were observed.

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The clinical effects of teicoplanin (TEIC) were investigated in 4 cases of postoperative abdominal wound infection caused by gram-positive bacteria. The causative organisms were methicillin-resistant Staphylococcus aureus (MRSA) in 2 cases and Enterococcus faecalis in 2 cases. The MIC of TEIC against 2 strains of E. faecalis was 0.2μg/ml, and 2 strains of MRSA were susceptible to TEIC.
Clinical response was good in 1, fair in 2 and poor in 1 case. The bacteriological response indicated a decrease in 2, no change in 1 and superinfection in 1 case. One patient with poor response had diffuse peritonits. TEIC plasma trough levels were maintained at around 5μg/ml with a dose of 200mg once a day. Side effects were not observed, except for eosinophilia in 1 case, which normalized rapidly after the completion of TEIC treatment.

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A newly developed glycopeptide group antibiotic, teicoplanin (TEIC), was intravenously infused (30 minutes) in 5 men and 2 women, inpatients of our department, and the efficacy of the drug and adverse reactions in infectious skin diseases were evaluated. On the first day, 200 to 400mg of TEIC was drip infused every 12 or 24 hours, thereafter, 200 to 400mg was given once a day. The clinical results revealed one markedly effective case, three effective cases and three obscure cases. The causative organisms disappeared in all cases. The sensitivity (inoculum size: 10⁶CFU/ml) to TEIC of all 5 isolates of Staphylococcus aureus whose MICs could be measured before treatment were 0.39μ/ml (2 strains) and 0.78μg/ml (3 strains). No adverse reactions or abnormal clinical laboratory findings attributable to the drug were observed.
From the above results, it was considered that TEIC is a useful drug for infectious disease in the area of dermatology, especially for methicillin-resistant S. aureus infection.

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Teicoplanin (TEIC) was used in 5 patients with skin and skin structure infection. TEIC was administered by intravenous injection of 400 mg over a 30-minute period once or twice a day on the first day of treatment followed by once a day treatment of 200mg or 400mg. Clinical response was evaluated in 4 patients. One patient dropped out due to superinfection with gramnegative bacilli. Overall clinical response was good in all 4 patients. Drug-induced fever was observed in one patient. Slight eosinophilia, elevation of CRP, lowering of creatinine clearance and elevation of γ-GTP were observed. All of these disappeared spontaneously after therapy.

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