IN VITRO INTERACTION OF AMINOGLYCOSIDES AND BETA-LACTAM PENICILLINS
| dc.creator | Chan, Grace Lap-Yu | |
| dc.date.accessioned | 2023-11-03T15:36:36Z | |
| dc.date.available | 2023-11-03T15:36:36Z | |
| dc.date.issued | 1984 | |
| dc.date.submitted | 1984 | en_US |
| dc.description.abstract | The aminoglycoside antibiotics are often used in combination with a f3-lactam antibiotic, to provide either a wider spectrum of activity against gram-negative bacilli or a synergistic antimicrobial effect against Pseudomonas aeruginosa and various enterobacteria. In 1971, MacLaughlin & Reeves found that the combined use of gentamicin and carbenicillin resulted in an interaction and loss of activity of both antibiotics. Since then more studies, in vitro and in vivo, have been performed to study the effect of medium, temperature, concentration, time, pH and different penicillin-aminoglycoside combinations on the interaction. The purpose of this study was to investigate the kinetics of the interaction in vitro. Four different concentrations of aminoglycosides (A) (5, 10, 15 & 20 pg/mL of gentamicin or tobramycin) and penicillins (P) (100, 200, 400 & 600 pg/mL of carbenicillin or ticarcillin) were incubated in plasma at 37°C for 3 days. Samples taken at 12 h intervals were analyzed for both aminoglycoside and penicillin by radioimmunoassay and high pressure liquid chromatography, respectively. Degradation of all four antibiotics in controls were first order reactions. The degradation of penicillins was faster than the aminoglycosides, with only 50% of the original concentration remaining at 24 h. In incubation mixtures, the rate of loss of penicillins was not significantly different from the controls and still appeared as a first order reaction. The interaction did not contribute significantly to the loss of penicillin. However, the rate of loss of aminoglycosides was greater than in controls and appeared as a second order reaction dependent on the concentration of both penicillin and aminoglycoside. The loss of aminoglycoside was due to its degradation in plasma and its interaction with penicillin. The degradation constants of penicillins (Kp) were calculated as dP/dt = -K PP and averaged 1.8 x 10 -2 h -1 for carbenicillin and 2.6 x 10 -2 h -1 for ticarcillin in controls and averaged 2.2 x 10 -2 h -1 for carbenicillin and 3.0 x 10 -2 h -1 for ticarcillin in antibiotic mixtures. In both controls and mixtures, the time required for loss of 50% of initial analyzed concentration (t50) was 30 & 55% larger, for carbenicillin and ticarcillin respectively, at higher penicillin concentrations of 400 & 600 µg/mL compared to lower penicillin concentrations of 100 & 200 µg/mL. The degradation constants of aminoglycosides (KA) in controls were calculated as dA/dt = -K A A and averaged 0.9 x 10 -3 h -1 for gentamicin and 1.2 x 10 -3 h -1 for tobramycin. The degradation constants of aminoglycosides in antibiotic mixtures and the interaction rate constants (K.) were determined by computer fitting of the aminoglycoside concentrations in incubation mixtures to a model incorporating a second order loss of aminoglycoside and a first order loss of penicillin from the mixtures. The degradation constants of aminoglycosides in antibiotic mixture were less than 1 x 10 -8 h -1 . The t 50 values of aminoglycosides in antibiotic mixtures were shorter than in controls (> 25 days) and were related to the concentration of penicillin. The t50 values of aminoglycosides were longer than 72 h at a penicillin concentration of 100 µg/mL. As the concentration of penicillin became higher, the t50 values became shorter and were less than 10 h for a penicillin concentration of 600 µg/mL. The interaction rate constants averaged 2.2 x 10-4 mL/µgxh and 1.6 x 10 -4 mL/µgxh for both carbenicillin and ticarcillin interactions with gentamicin and tobramycin, respectively. The "effective" interaction rate constants (K. x P) were larger for the higher penicillin concentrations. Examination of both the t 50 values of aminoglycosides and the K. indicated that there was no significant difference between the interaction rate produced by carbenicillin and ticarcillin and gentamicin was inactivated more by carbenicillin and ticarcillin than tobramycin. The effect of the interaction in vivo was examined by computer simulation using the kinetic parameters determined in vitro. The interaction of penicillin and aminoglycoside would be significant in patients with impaired renal function and might be significant in patients with normal renal function when the concentration of penicillin is very high. | en_US |
| dc.identifier.uri | https://hdl.handle.net/10388/15209 | |
| dc.subject | aminoglycoside antibiotics | en_US |
| dc.subject | ß-lactam antibiotic | en_US |
| dc.subject | penicillin-aminoglycoside | en_US |
| dc.title | IN VITRO INTERACTION OF AMINOGLYCOSIDES AND BETA-LACTAM PENICILLINS | en_US |
| dc.type.genre | Thesis | en_US |
| thesis.degree.department | Pharmacy and Nutrition | en_US |
| thesis.degree.grantor | University of Saskatchewan | en_US |
| thesis.degree.level | Masters | en_US |
| thesis.degree.name | Master of Science (M.Sc.) | en_US |