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Studies on the Synergism of Ciprofloxacin with beta-Lactam Antibiotics, Gentamicin, Minocycline and Pipemidic Acid. Using Escherichia coli, Klebsiella pneumoniae/Klebsiella oxytoca, Pseudomonas aeruginosa and Staphylococcus aureus strains, we examined a possible influence of pipemidic acid, minocycline, gentamicin, cefazolin, mezlocillin and ampicillin on the antibiotic activity of ciprofloxacin. We found in all bacterial species synergistic influence by pipemidic acid. When ciprofloxacin was combined with gentamicin, synergism was observed in E. coli and in K. pneumoniae/oxytoca, additive effects in P. aeruginosa and S. aureus. In combination with minocycline we demonstrated synergism in S. aureus only. In all other bacterial species and antibiotic combinations we found neither synergism nor antagonism.

The influence of nutrient-broth (NB), Mueller-Hinton-broth (MHB), isotonic-sensitive-broth (ISB) and tryptone-soya-broth (TSB) with respect to the determination of MIC values of three tetracyclines is shown. A difference of degradation of tetracycline derivates in the four media was found. The degradation in NB after 18 h was negligible, but in MHB after 18 h all the three tetracyclines were inactivated up to 42%. The MIC levels of staphylococcus aureus strains in NB were about twofold lower than those in MHB and TSB. The MIC levels in ISB were even three- to fourfold higher than in NB. From these results sensitivity testing of tetracycline derivates should be carried out with NB.

A staphylococcus aureus strain of a patient with plasmidical tetracyclinresistance has first been cured from the plasmid and after that selected in nutritive broth by increasing the concentrations of tetracyclin. By this way we found three variants of the same strain: a tetracyclin-sensitive and two tetracyclin-resistant: an R-plasmid-mediated and the other as a result of mutation. These three variants have been tested against tetracyclin, minocyclin and doxycyclin on an agarmedium. Under influence of these three substances a microcalorimetrical investigation of the strains has taken place. We then tested the strains with the electronic microscope for alterations in the ultra-structure by the three substances. Following results have been obtained: 1. The sensitive strains were inhibited in the same extent by all of the three substances. Plasmidical resistant strains were only resistant against tetracyclin but not against minocyclin and even less against doxycyclin. 2. The microcalorimetrical tests confirmed the conclusions from the cultural test. 3. Alterations in ultra-structure were only found under tetracyclin-influence by strains in division. Comparing the three tetracyclines we did not find any significant difference in quality. 4. With all of the three investigation-methods we proved that R-plasmid-mediated tetracyclin-resistance of staphylococci is not effective for minocyclin and even less for doxycyclin.

The in vitro activity of doxycycline and minocycline (Klinomycin) was determined by serial dilution test in 100 strains of E. coli, 101 strains of enterobacter, 91 tetracycline-sensitive and 52 tetracycline-resistant strains of staphylococci. Only staphylococci were more sensitive against minocycline than against doxycycline whereas other species showed nearly the same sensitivity against both antibiotics. After i.v. infusion of 200 mg minocycline (during 1 h) mean serum levels fell from 3.5 mug/ml to 0.6 mug/ml (after 24 h). Half-life was calculated as 15.7 h, urine recovery as 5.9%. After oral application of 200 mg minocycline serum level peaks were 2.7 mug/ml, serum levels after 24 h 0.7 mug/ml. At repeated administrations daily dosage of 100 mg was too low of 200 mg sufficient to obtain the same serum levels as after the initial dose of 200 mg. CSF levels after oral administration of 0.4 g minocycline were 0.74 +/- 0.09 mug/ml (in serum at the same time 2.2 +/- 0.2 mug/ml). Half-life of minocycline in chronic renal failure (7 adult patients) was not prolonged (15--20 h). Minocycline is especially suitable for treatment of infections of unknown bacterial origin (including such caused by staphylococci). I.v. infusion is indicated only in unconscious or vomiting patients.

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.