coumermycin and Staphylococcal-Infections

In vitro, coumermycin (a bis-hydroxicoumarin gyrase inhibitor) proved significantly more active than ofloxacin and vancomycin against 100 strains of methicillin-resistant Staphylococcus aureus (MRSA). The MIC90 was 0.5 microgram/ml, whereas the corresponding figures for the other antimicrobials were 2.0 and 4.0 micrograms/ml. In vivo, an otherwise lethal septicemia, induced by intraperitoneal administration of a MRSA in mice, was "successfully treated" in 50% of the animals (ED50) with the following dosages (microgram/g b. wt.): coumermycin 0.9, ofloxacin 10.8, vancomycin 22.4. The ED50 of coumermycin was significantly (2 p less than 0.01) different from those of the other drugs. Renal infection as produced in mice by transcutaneous inoculation of the same MRSA was treated with either of the antimicrobials at different dosages (single doses of 0.0 or 1.6 or 6.3 or 25.0 micrograms/g b. wt., twice daily) during 6 days. The largest reductions of viable counts in the kidneys at each dosage as compared to the bacterial counts of untreated animals were achieved with coumermycin (3.4 or 5.5 or 7.7 log10). These reductions are significantly (2 p less than 0.01) different from those achieved with the comparable dosages of ofloxacin and vancomycin which were 0.1 or 1.8 or 2.8 and 0.4 or 1.4 or 3.0 log10 respectively. After a single subcutaneous injection of 250 micrograms mean concentrations in serum of mice for coumermycin were 6.2-5.0 micrograms/ml for 8 h, for ofloxacin 2.0-0.5 micrograms/ml for 2 h, and for vancomycin 14.7-2.5 micrograms/ml for 2 h. Coumermycin and ofloxacin could be alternatives to vancomycin in the therapy of human infections due to MRSA.

Topics: Aminocoumarins; Animals; Anti-Bacterial Agents; Coumarins; Drug Resistance, Microbial; Male; Methicillin; Mice; Mice, Inbred Strains; Microbial Sensitivity Tests; Ofloxacin; Oxazines; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

The efficacy of a 5-day treatment with coumermycin A1 (hereafter referred to as coumermycin) (at three dosage regimens), with ciprofloxacin, or with coumermycin plus ciprofloxacin was tested in experimental aortic valve endocarditis induced in rats by a strain of methicillin-susceptible Staphylococcus aureus and was compared with the efficacy of a 5-day treatment with cloxacillin plus gentamicin. While coumermycin was far less effective than cloxacillin plus gentamicin in reducing the bacterial counts in vegetations (P less than 10(-8), ciprofloxacin was as effective as cloxacillin plus gentamicin. Coumermycin plus ciprofloxacin was less effective than ciprofloxacin alone (P = 0.01). For endocarditis induced by two additional methicillin-susceptible S. aureus strains, the high-dosage regimen of coumermycin (12 mg/kg every 12 h) had the same low efficacy. Coumermycin-resistant variants of S. aureus emerged in most of the vegetations during coumermycin treatment. The ciprofloxacin susceptibility of S. aureus was unchanged during ciprofloxacin treatment. The addition of ciprofloxacin to coumermycin in the treatment did not prevent the emergence of coumermycin-resistant variants. Twelve additional S. aureus strains isolated from the blood of patients with endocarditis were tested in vitro against coumermycin with precautions to avoid carry-over of the antibiotic. Coumermycin exhibited a bacteriostatic activity at very low concentrations (MIC, less than 0.004 microgram/ml) but only a weak bactericidal activity (MBC for 90% of strains, 8 micrograms/ml), a finding contrasting with that of others. Furthermore, coumermycin-resistant mutants could be selected in vitro from the 15 S. aureus strains tested. These results indicated no evidence in vivo of a synergistic activity of coumermycin and ciprofloxacin. More importantly, these results suggested that coumermycin might not be adequate for the treatment of serious s. aureus infections in humans.

Topics: Aminocoumarins; Animals; Ciprofloxacin; Cloxacillin; Coumarins; Drug Evaluation, Preclinical; Drug Therapy, Combination; Endocarditis, Bacterial; Gentamicins; Humans; Microbial Sensitivity Tests; Rats; Staphylococcal Infections; Staphylococcus aureus

The in vitro activity of coumermycin, fusidic acid, cotrimoxazole, and vancomycin was determined by broth microdilution assay against 33 methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates from the Detroit Receiving Hospital, Detroit, Mich. Coumermycin was the most active drug tested, while fusidic acid, vancomycin, and cotrimoxazole also had good activity. The four antimicrobials were tested in vivo against 7 strains of MRSA employing the mouse protection model. Again, coumermycin was the most active, followed by vancomycin, cotrimoxazole, and fusidic acid. Coumermycin was very active, while vancomycin and fusidic acid were inactive in neutropenic mice infected with an MRSA strain. Coumermycin retained activity when given 18 h before an MRSA infection, while vancomycin activity was lost. Coumermycin was active in a local thigh infection while vancomycin was inactive. The results indicate that coumermycin is potent against MRSA with activity equal or superior to comparable agents in various experimental mouse infections.

Topics: Aminocoumarins; Animals; Anti-Bacterial Agents; Coumarins; Drug Combinations; Female; Fusidic Acid; Methicillin; Mice; Microbial Sensitivity Tests; Neutropenia; Penicillin Resistance; Staphylococcal Infections; Staphylococcus aureus; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

Topics: Aminocoumarins; Coumarins; Humans; Methicillin; Microbial Sensitivity Tests; Penicillin Resistance; Staphylococcal Infections; Staphylococcus