In vitro antimicrobial activity of the thiazolyl peptide antibiotic MDL 62,879 (GE2270 A).

Compound MDL 62,879 (GE2270 A) is a thiazolyl peptide antibiotic that appears to inhibit aminoacyl-tRNA binding to elongation factor Tu. In the present study, it was shown that MDL 62,879 broth microdilution MIC values were generally 2-4 doubling dilutions lower in the presence of 0.02% bovine serum albumin. Using US clinical isolates and BSA-supplemented media, MDL 62,879 was more active than teicoplanin and vancomycin against the staphylococci and glycopeptide-resistant and glycopeptide-susceptible enterococci and equally active against the streptococci. Broth microdilutions MIC values were not appreciably affected by inoculum concentrations of 5 x 10(4) to 5 x 10(8) cfu/ml or in the presence of 3.5% human serum albumin.

Comparison of biological and chemical assays for the quantitation of rifapentine in human plasma.

The purpose of this study was to establish the correlation between biological and chemical assays for the quantification of rifapentine in human plasma. The bioassay was found to overestimate antibiotic plasma concentration when compared to the high-performance liquid chromatography (HPLC) assay for rifapentine (r = 0.9538, n = 220). This was because of the presence of varying amounts of the biologically active 25-O-desacetyl metabolite in the test samples. A better correlation (r = 0.9804, n = 220) was observed when the bioassay data were compared to combined parent-metabolite HPLC values. Such correlative data are necessary adjuncts in the establishment of antibiotic susceptibility test breakpoints.

In vitro activity of the semisynthetic glycopeptide amide MDL 63,246.

The in vitro activity of the semisynthetic glycopeptide amide MDL 63,246 against 293 U.S. clinical isolates of gram-positive cocci was determined by the broth microdilution method. When compared with teicoplanin, MDL 63,246 had improved activity against Staphylococcus epidermidis (MICs that inhibited 90% strains tested [MIC90s], 0.25 versus 8 micrograms/ml, respectively). Staphylococcus haemolyticus (MIC90s, 1 versus 32 micrograms/ml, respectively), and VanA Enterococcus faecium (MIC90s, 32 versus > or = 1,024 micrograms/ml, respectively).

Comparison of agar dilution, tube dilution, and broth microdilution susceptibility tests for determination of ramoplanin MICs.

Standard broth microdilution (with and without bovine serum albumin [BSA] supplementation), tube dilution, and agar dilution susceptibility tests were compared for determining ramoplanin MICs. With a data base of 246 clinical isolates of gram-positive bacteria from 33 U.S. sites, it was shown that (i) agar and tube dilution susceptibility tests gave essentially the same results (93.9% of the test results were within 1 doubling dilution of equivalence), (ii) broth microdilution susceptibility tests gave results up to 5 doubling dilutions higher than agar or tube assays, and (iii) this data skewing could be reversed by BSA supplementation (final concentration, 0.02%) of the broth microdilution test medium.

Bioassay quantitation of ramoplanin in human and in nonprimate sera.

This study developed and validated a bioassay for ramoplanin in human, dog, rabbit, and rat sera. Mean analyte recoveries and coefficients of variation for duplicate assays with each serum using coded and spiked (30-720 ng/ml) samples ranged from 93.5% to 106.3% and from 1.8% to 5.4% respectively. All correlation coefficients were > 0.99 and, for each serum, there was no significant difference in overall analyte recovery between the 2 test days.

Evaluation of the teicoplanin broth microdilution and disk diffusion susceptibility tests and recommended interpretive criteria.

Comparative teicoplanin in vitro susceptibility data were generated for 1201 Gram-positive US clinical trial isolates using standardized broth microdilution and disk diffusion techniques. Based on the results of this study, the following interpretive criteria for teicoplanin are recommended: for MIC tests, less than or equal to 8 micrograms/ml = susceptible, 16 micrograms/ml = moderately susceptible, and greater than or equal to 32 micrograms/ml = resistant; and for disk (30 micrograms) tests, greater than or equal to 14 mm = susceptible, 11-13 mm = intermediate, and less than or equal to 10 mm = resistant.

Pharmacokinetics of teicoplanin upon multiple-dose intravenous administration of 3, 12, and 30 milligrams per kilogram of body weight to healthy male volunteers.

Teicoplanin pharmacokinetics were evaluated after multiple-dose intravenous administration to healthy male volunteers by using a randomized, double-blind, parallel design. Doses of 3, 12, or 30 mg of teicoplanin per kg of body weight were administered every 24 h for 14 days as 60-min constant-rate intravenous infusions. Blood and urine samples were collected over 21 days and analyzed by a microbiological assay. Twenty-three subjects were included in the pharmacokinetic analysis. The median pharmacokinetic parameters upon multiple-dose intravenous administration of 3, 12, and 30 mg/kg included steady-state volumes of distribution of 0.94, 0.77, and 0.68 liter/kg; total clearances of 11.9, 12.0, and 13.2 ml/h/kg; and terminal disposition half-lives of 143, 166, and 96 h, respectively. Renal clearance accounted for approximately 95% of total clearance. No dose-related differences existed for teicoplanin total or renal clearance. The steady-state volume of distribution decreased significantly with increasing doses. As a result of the decrease in the volume of distribution, the terminal disposition half-life at 30 mg/kg was significantly decreased. However, the decreases in the volume of distribution and terminal disposition half-life are of limited clinical importance, since steady-state trough concentrations in serum increase in proportion to dose. Combined results of all multiple-dose studies with similar durations of sample collection indicate no dose-related differences for any pharmacokinetic parameters from 3 to 12 mg/kg. As observed in the present study, no dose-related differences exist for teicoplanin total and renal clearances from 3 to 30 mg/kg. However, at 30 mg/kg, a significant decrease in the steady-state volume of distribution is observed. As a consequence of the reduction in the volume of distribution at 30 mg/kg with no change in clearance, the terminal disposition half-life is decreased.

Pharmacokinetics and bioavailability of a new formulation of teicoplanin following intravenous and intramuscular administration to humans.

Pharmacokinetics, bioavailability, and local tolerance (at the site of intramuscular administration) of a new formulation of teicoplanin (400 mg/3 mL) were investigated in 24 normal, healthy, male volunteers. A single dose of 6 mg/kg was administered intravenously and intramuscularly using a randomized crossover design. Volunteers and investigator were blinded as to the route of administration; placebo was administered by the other route. Blood and urine samples were collected for 21 days and were analyzed for microbiological activity. The median (range) pharmacokinetic parameters of teicoplanin following single-dose iv administration were as follows: steady-state volume of distribution of 1.6 (1.2-2.8) L/kg; total clearance of 10.2 (8.6-15.1) mL/h/kg; renal clearance of 10.0 (7.9-13.8) mL/h/kg; and terminal disposition half-life of 168 (111-278) h. Following single-dose im administration, significantly more subjects complained of pain following administration of teicoplanin (58%) compared with placebo (4%). Teicoplanin was completely absorbed with a median (range) peak serum concentration of 12.3 (6.6-37.5) micrograms/mL occurring at a median (range) time of 4.1 (0.7-6.1) h. Since the 90% confidence interval for the ratio of areas under the serum concentration-time curve falls within the range of 80 to 120%, the extent of systemic absorption of teicoplanin following im administration is equivalent to that following iv administration.

Comparative in vitro activity of teicoplanin and vancomycin against United States teicoplanin clinical trial isolates of gram-positive cocci.

In this study, the in vitro activity of teicoplanin and vancomycin was directly compared against 503 Gram-positive cocci isolated during the U.S. teicoplanin clinical trials. Both antibiotics were equally active against oxacillin-sensitive Staphylococcus aureus, oxacillin-sensitive and oxacillin-resistant Staphylococcus epidermidis, and other coagulase-negative staphylococci, except Staphylococcus haemolyticus. Teicoplanin was fourfold more active than vancomycin against oxacillin-resistant S. aureus (MIC90, 0.5 vs. 2.0 micrograms/ml), whereas vancomycin was more active than teicoplanin (MIC90, 2.0 vs. 8.0 micrograms/ml) against oxacillin-resistant S. haemolyticus. Teicoplanin was two- to eightfold more active than vancomycin against the streptococci and enterococci tested.

Bioassay of teicoplanin in serum containing rifampin or a beta-lactam antibiotic.

The purpose of this study was to develop bioassays for the measurement of teicoplanin in serum containing rifampin or a beta-lactam antibiotic. Use of rifampin-resistant Bacillus subtilis as indicator organism or pretreatment of the serum sample with Bacillus cereus penicillinase Type I (nafcillin, ticarcillin, mezlocillin) or Type II (cefazolin, cefuroxime, ceftazidime, ceftriaxone) effectively eliminated assay interference. Validation bioassays performed on two separate days utilizing triplicate coded serum samples containing 0 to 200 micrograms teicoplanin in combination with 40 micrograms/ml rifampin or 200 to 500 micrograms/ml beta-lactam showed no significant differences (p greater than 0.05, two-way analysis of variance) in analyte recovery between assay days. Regression analysis of each teicoplanin/rifampin or teicoplanin/beta-lactam data set yielded slope values of 0.92 to 1.01, intercept values of -0.45 to 0.84 and correlation coefficients of 0.9925 to 0.9990. Thus, serum teicoplanin can be quantitated accurately, precisely, and reproducibly in patients receiving concomitant rifampin or beta-lactam chemotherapy.

Comparison of the agar dilution, tube dilution, and broth microdilution susceptibility tests for determination of teicoplanin MICs.

The purpose of this study was to evaluate the National Committee for Clinical Laboratory Standards agar dilution, tube dilution, and broth microdilution susceptibility tests for the measurement of teicoplanin MICs. The three standardized tests gave equivalent (within a twofold dilution) results with 98.8 to 99.0% of the 508 gram-positive clinical isolates tested, indicating that either method may be used for teicoplanin MIC determination.