[Experimental study of antibacterial activity, therapeutic effectiveness and toxic properties of the combination of tobramycin and carbenicillin]. / Eksperimental'noe izuchenie antibakterial'noi aktivnosti, terapevticheskoi éffektivnosti i toksicheskikh svoistv kombinatsii tobramitsina s karbenitsillinom.

Tobramycin combination with carbenicillin was studied experimentally. Tobramycin is a new aminoglycoside antibiotic prepared at the Institute of New Antibiotics, the USSR Academy of Medical Sciences. It was shown that the combination had mainly synergistic action (67 per cent) on clinical strains of Pseudomonas aeruginosa which was confirmed in treatment of experimental sepsis caused by the organism. In acute experiments with albino mice there was observed summation of the general toxic action of the antibiotics used in the combination. The level and nature of the nephrotoxic action of the tobramycin combination with carbenicillin were shown in experiments with rats to be the same as those of the nephrotoxic action of tobramycin used alone. The presence of carbenicillin in the combination did not increase the inhibitory effect of tobramycin on excitement transmission in the neuromuscular synapses.

A polyphosphate kinase 1 (ppk1) mutant of Pseudomonas aeruginosa exhibits multiple ultrastructural and functional defects.

Pseudomonas aeruginosa, of medical, environmental, and industrial importance, depends on inorganic polyphosphate (poly P) for a wide range of functions, especially survival. Mutants of PAO1 lacking poly P kinase 1, PPK1, the enzyme responsible for most poly P synthesis in Escherichia coli and other bacteria, are defective in motility, quorum sensing, biofilm formation, and virulence. We describe here multiple defects in the ppk1 mutant PAOM5, including a striking compaction of the nucleoid, distortion of the cell envelope, lack of planktonic motility and exopolymer production, and susceptibility to the beta-lactam antibiotic carbenicillin as well as desiccation. We propose that P. aeruginosa with reduced poly P levels undergoes ultrastructural changes that contribute to profound deficiencies in cellular functions.

In vitro and in vivo cytogenetic studies of three beta-lactam antibiotics (penicillin VK, ampicillin and carbenicillin).

The in vitro and in vivo clastogenic potential of three beta-lactam antibiotics, ampicillin, carbenicillin and penicillin VK, was investigated using cultured human lymphocytes and the rat micronucleus test. Neither ampicillin nor carbenicillin induced significant increases in chromosome damage in vitro up to test concentrations of 10 mg/ml. These results contrast with other published studies on these compounds. Both drugs were also inactive in vivo in the rat micronucleus test, using single- or double-dosing regimens (ampicillin 5 g/kg orally; carbenicillin 500 mg/kg i.m., either dosed once 30 h before marrow preparation, or dosed twice 48 and 24 h before marrow preparation). In vitro, penicillin VK induced a dose-related increase in chromosome and chromatid gaps and breaks, down to concentrations of 1.25 mg/ml. It is likely that the increase in aberration frequency was partly the result of exposing the cells to increased K+ ion concentration, as similar results were obtained when potassium chloride was evaluated over the same molar concentration range. However, the occurrence of 'ion-mediated' clastogenic effects as reported by other workers, does not fully account for the positive effects obtained with this compound, as clastogenic effects were also observed with penicillin V in this test system at similar test concentrations. It is known that exposure of mammalian cells to extremely high concentrations of beta-lactams can affect DNA polymerase alpha activity. An inhibitory effect upon DNA polymerase alpha resulting in a breakdown in the structural integrity of the chromosomes, is suggested as an additional mechanism of action for penicillin VK.(ABSTRACT TRUNCATED AT 250 WORDS)

[Experimental study of the toxic effect of combinations of tobramycin and carbenicillin]. / Issledovanie toksicheskogo deistviia kombinatsii tobramitsina s karbenitsillinom v éksperimente.

Acute toxicity of tobramycin and carbenicillin used alone and in combination was studied on albino mice. The antibiotics were combined in the following ratios: 1:15, 1:30, 1:45, 1:60, 1:75 and 1:150 (1 refers to tobramycin). The character of the toxic effect of the combinations was estimated with the Loewe graphical method and interaction indices. It was shown that interaction of tobramycin with carbenicillin in the combinations with wide ratio ranges was of an indifferent character. The toxic effect of the combinations did not reach the total toxic effect of the components used alone. It was noted that the combinations of tobramycin with carbenicillin in the ratios of 1:15, 1:30 and 1:150 were most favourable for the drug tolerance. The nephrotoxic effect of tobramycin and carbenicillin used alone and in combination was studied on albino rats. The antibiotics were administered intravenously for 5 days. It was demonstrated that the level and the character of the morphological changes in the kidneys of the rats treated with the combinations of tobramycin and carbenicillin were the same as those after the use of an analogous dose of tobramycin alone. Therefore, the nephrotoxic effect of tobramycin was not potentiated on its combined use with carbenicillin.

Evaluation of genotoxicity of ampicillin and carbenicillin on human lymphocytes in vitro: chromosome aberrations, mitotic index, cell cycle kinetics, satellite associations of acrocentric chromosomes and sister chromatid exchanges.

A large number of drugs have been introduced into man's environment in recent years, many of which have been shown to have mutagenic, teratogenic and carcinogenic effects. Keeping in view the potential hazardous effects of drugs and chemicals, it is desirable to test new drugs for their genotoxic effects prior to widespread use. In the present investigation genetic effects of ampicillin and carbenicillin were studied in vitro in human lymphocytes using a number of end-points. These drugs were added at a range of concentrations and times during a 72h culture period. Concentrations corresponding to the plasma level after receiving therapeutic doses as well as concentrations higher than the plasma levels were examined. Neither drug affected the frequency of chromosome aberrations, satellite associations, mitotic index and cell turnover rate at plasma level concentrations. However, all these parameters were affected at higher concentrations. The frequency of SCEs was not increased with both the drugs irrespective of the concentrations or durations of treatment, suggesting that the mechanisms leading to the formation of SCEs and chromosome aberrations are different. Both ampicillin and carbenicillin were genetically non-toxic for the end points measured and non-clastogenic in vitro at therapeutic doses. However, previous studies have shown ampicillin to be clastogenic in vivo. For evaluation of genetic toxicity, drugs should be tested both in vitro and in vivo.