Treatment of experimental cryptococcal meningitis and disseminated candidiasis with SCH39304.

We studied the pharmacokinetics and in vivo antifungal action of SCH39304, a new antifungal azole compound, in rabbits. It crossed the blood-cerebrospinal fluid barrier in the presence or absence of meningeal inflammation, reaching approximately 60% of the simultaneous concentrations in serum. In the treatment of experimental cryptococcal meningitis, SCH39304 was as effective as fluconazole in reducing yeast counts in the subarachnoid space. SCH39304 and fluconazole both were highly effective against candida endophthalmitis, sterilizing the vitreous humor and the choroid and retina. SCH39304 suppressed candida endocarditis and reduced yeast counts in the kidney at all doses tested. SCH39304 was effective in the treatment of experimental cryptococcal meningitis and disseminated candidiasis. Further investigations in humans are warranted.

Comparison of amphotericin B and N-D-ornithyl amphotericin B methyl ester in experimental cryptococcal meningitis and Candida albicans endocarditis with pyelonephritis.

Amphotericin B and N-D-ornithyl amphotericin B methyl ester were compared for therapeutic efficacies against experimentally induced cryptococcal meningitis and Candida albicans endocarditis with pyelonephritis in rabbits. Antifungal activity of the two polyenes in vitro was similar for the yeasts used in these experiments. N-D-ornithyl amphotericin B methyl ester gave a slightly higher concentration in serum than amphotericin B did, but both drugs had similar elimination curves, and penetration into the cerebrospinal fluid was poor for both. Despite these similarities between the two polyenes, amphotericin B was much more effective than N-D-ornithyl amphotericin B methyl ester in the treatment of cryptococcal meningitis in rabbits. For C. albicans endocarditis, both polyenes had similar cure rates, but in vitro measurement of fungicidal activity in serum did not predict treatment outcome. For C. albicans pyelonephritis, both polyenes showed efficacy; because higher doses of the less toxic methyl ester could be used, it sterilized the urinary tract more often than amphotericin B. These studies indicate that in vivo and in vitro experiments may be needed to predict the results of treatment with polyenes.

Therapeutic significance of penicillin tolerance in experimental streptococcal endocarditis.

Tolerance to penicillin exists among the viridans group of streptococci, but its therapeutic significance is unknown. We studied the effect of penicillin alone and in combination with streptomycin, in vivo and in vitro, on three strains of dextran-producing Streptococcus sanguis serotype II which possess widely various degrees of penicillin tolerance. In rabbits with experimental endocarditis, treatment with procaine penicillin (250 mg/kg intramuscularly twice daily for 5 days) decreased the number of viable organisms in valvular vegetations from 8.82 log10 +/- 0.98 CFU/g in untreated controls to 5.31 +/- 1.19 for a highly tolerant strain, 4.22 +/- 1.05 for a less tolerant strain, and 1.79 +/- 1.72 for a nontolerant strain (P less than or equal to 0.01 for comparison between any of the four groups). None of 36 rabbits infected with tolerant strains were cured by 5 days of treatment with penicillin, but 10 of 23 animals infected with the nontolerant strain were cured (P = 0.00002). When streptomycin was given in combination with penicillin, rabbits infected with the nontolerant strain were cured within 3 days, and rabbits infected with the tolerant strain were cured within 5 days. These findings indicate that tolerance can exert a critical influence on the response of S. sanguis to penicillin therapy in vivo and that the combination of penicillin plus streptomycin exerts a synergistic effect against tolerant as well as nontolerant organisms.

Trimethoprim-sulfamethoxazole vs. ampicillin in the treatment of experimental meningitis due to Streptococcus pneumoniae.

When given in combination, both trimethoprim and sulfamethoxazole penetrated well into the cerebrospinal fluid of rabbits with experimental pneumococcal meningitis, reaching concentrations that should have been adequate for synergistic killing of Streptococcus pneumoniae. However, trimethoprim-sulfamethoxazole was less effective than ampicillin in the treatment of this experimental infection. The effect of the combination on pneumococci in vivo was bacteriostatic rather than bactericidal, possibly because the number of pneumococci in the cerebrospinal fluid of the rabbits at the start of treatment was larger than that in the inoculum used for in vitro sensitivity tests.

Comparison of cotrimoxazole, ampicillin, and chloramphenicol in treatment of experimental Haemophilus influenzae type B meningitis.

To evaluate cotrimoxazole in the treatment of bacterial meningitis, we compared its action with that of ampicillin and chloramphenicol in experimental Haemophilus influenzae type b meningitis. Both trimethoprim and sulfamethoxazole penetrated well into the cerebrospinal fluid of infected rabbits, reaching 40 and 26%, respectively, of their simultaneous serum levels. Levels measured 30 and 60 min after intravenous injection exceeded the minimum inhibitory concentration of this combination for H. influenzae by 10- to 100-fold. The mean ratio of trimethoprim to sulfamethoxazole in cerebrospinal fluid was 1:22. Cotrimoxazole was as effective as ampicillin in therapy of beta-lactamase-negative H. influenzae meningitis and as effective as chloramphenicol for a beta-lactamase positive strain. These findings corroborate favorable preliminary clinical experience reported by others and indicate that cotrimoxazole deserves further study in the therapy of bacterial meningitis.

Effect of antibiotics on the prevention of experimental Bacteroides fragilis endocarditis.

The relative efficacy of single doses of antibiotics in modifying the development of Bacteroides fragilis subsp. fragilis endocarditis was studied in an experimental model. Antibiotics were administered 0.5 h before intravenous injection of B. fragilis subsp. fragilis into rabbits prepared by insertion of a polyethylene catheter into the left side of the heart; 48 h later, intracardiac vegetations were excised and cultured anaerobically. B. fragilis was recovered from 92% of untreated animals. After a single dose of procaine penicillin G (250 mg/kg intramuscularly), 80% of the animals remained infected. Chloramphenicol (30 mg/kg), carbenicillin (50 mg/kg), and metronidazole (10 mg/kg) were also ineffective (76, 80, and 75% infected, respectively). Cefamandole (30 mg/kg), cefoxitin (30 mg/kg), and erythromycin (30 mg/kg) were significantly more active (50, 55, and 45% infected, respectively), as were higher doses of carbenicillin. Clindamycin (50 mg/kg) was the most effective regimen (11% infected). At present, the relevance of these results to the therapy of serious B. fragilis infections is not known, but this model may prove useful in the evaluation of the prevention of B. fragilis subsp. fragilis bacteremia.