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In vitro and in vivo effects of combinations of cefotaxime or other beta-lactams with rolitetracycline on methicillin-resistant Staphylococcus aureus.

Combinations of cefotaxime (CTX) or other five beta-lactams with rolitetracycline (RTC) were examined using the checkerboard method for their synergistic effects against 27 strains of methicillin-resistant Staphylococcus aureus (MRSA), and the combination of CTX and RTC was further evaluated for its synergistic effect in vitro and in vivo against 1 or 2 strains. Synergy occurred against 44% of the strains when RTC was combined with CTX, 22 to 30% with cefazolin, methicillin, and ceftizoxime, and 4 to 11% with latamoxef and cefmetazole. No antagonism was found with any combinations tested. Killing curve studies also showed that CTX/RTC was synergistic between 3 and 24 hours after the beginning of exposure, and the synergy was especially strong at 24 hours and potencies of combined bactericidal effect determined at 24 hours were in the following order: the 2 antibiotics given simultaneously, CTX given 2 hours before RTC, and CTX given 2 hours after RTC. In addition, the 2 drugs in combination synergistically inhibited (a) mortality in mice infected intraperitoneally with MRSA and (b) formation of subcutaneous abscess induced by MRSA in mice. The results of our study indicate that beta-lactams, especially CTX, had synergistic effects in vitro when combined with RTC against MRSA and that the combination of CTX and RTC was also synergistic in vivo.

Animals↗

[Tetracyclines: bacteriostatic or bactericidal drugs? In vitro studies with rolitetracycline, minocycline and doxycycline (author's transl)].

Minimal bacteriostatic and minimal bactericidal concentrations of rolitetracycline, minocycline and doxycycline on 20 different E. coli serotypes and 16 staphylococcus aureus strains have been compared in bouillon and serum. In addition growth curves of all strains in bouillon and serum without and with antibiotics in concentrations corresponding to the minimal inhibitory concentration of each strain have been followed for 24 hours. In E. coli minimal bactericidal concentrations of all 3 tetracyclines in bouillon on average were only twice as high as the minimal bacteriostatic concentrations of the drugs, tested. Minimal bacteriostatic and bactericidal concentrations in serum were significantly lower than in bouillon. 27 out of 20 E. coli strains were inhibited by less than 0.012 microgram/ml. In staphylococci minimal bactericidal concentrations were substantially higher than the minimal bacteriostatic concentrations (on average at least four times higher). In E. coli addition of serum increased the antimicrobial activity of all tetracyclines tested. Growth curves in bouillon tended to show some bactericidal shape at 3, 7 and 24 hours following addition of the tetracyclines at minimal bacteriostatic concentrations. Bactericidal activity of tetracyclines at the MIC was substantially improved by addition of serum. This was not true for staphylococci in which neither minimal bactericidal and bacteriostatic concentrations nor growth curves could be significantly improved by addition of serum.

Doxycycline↗

The international standard for rolitetracycline.

An International Standard for Rolitetracycline has been established and the international unit of this antibiotic defined as the activity contained in 0.001004 mg of the international standard. The definition of the international unit was based on the results of a collaborative assay in which 8 laboratories in 6 different countries participated; a total of 133 assays were performed. The assay was in terms of the Working Standard of the USA Food and Drug Administration; mean potencies for individual laboratories varied within a range of only 2% of the mean for all assays although 7 different test organisms were used in both diffusion and turbidimetric assays. Individual assays, however, provided potencies that varied within a range of 40%.

International Cooperation↗

Comparative evaluation of the effects of tetracycline, rolitetracycline and doxycycline on some blood parameters related to liver function.

A comparative study was made on the effects of tetracycline (TC), rolitetracycline (RTC), and doxycycline (DC) at doses of 10-100 micrograms/g i.v. on serum GOT, GPT, bilirubin and urea levels of male and female mice. All tetracyclines at doses of 50-100 micrograms/g caused an increase of serum GOT and GPT activities in females after 2-8 h. This effect was less pronounced in males. The serum urea levels were markedly raised by TC and DC (50-100 micrograms/g) and RTC (10-100 micrograms/g). This effect was produced only in females. It was long-lasting (up to 8 h) after TC and RTC and more transient after DC. Likewise the tetracyclines affected the serum bilirubin only in females but not in males. All tetracyclines (25-100 micrograms/g) increased the amount of unconjugated and total bilirubin. This effect was most pronounced after TC, which also reduced the level of conjugated bilirubin.

Alanine Transaminase↗

Distribution of pyrrolidinomethyl-tetracycline (rolitetracycline) and tetracycline in blood and various organs of mice measured by high pressure liquid chromatography.

By means of a newly developed high-pressure liquid chromatographic method the organ distribution of tetracycline (TC) and pyrrolidinomethyl-tetracycline (PMT) has been studied. When mice were treated with 50 mg/kg i.v. TC or PMT these antibiotics could be detected in all organs investigated (liver, kidney, heart, lung, muscle, spleen). Especially high concentrations were found in liver and kidneys, where TC and PMT could be detected up to 6 h. In animals treated with PMT part of the PMT applied decomposed slowly yielding TC, which was found together with PMT in blood and all organs.

Animals↗