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Of 22 patients who were suspected of having bacterial endocarditis and who were treated with cefoxitin intravenously (8-12 g per day), 12 were evaluated for responses to therapy. Ten patients had infections due to a single pathogen, and two had polymicrobial infections. Staphylococci were isolated from eight patients, and streptococci from four; both of these pathogens were susceptible to 2-16 micrograms of cefoxitin/ml. Staphylococcus aureus and four strains of anaerobic bacteria, including Bacteroides fragilis (minimal inhibitory concentration, 32 micrograms/ml), were isolated from one patient. The average level of cefoxitin in serum was 32.8 micrograms/ml (range, 14.5-64 micrograms/ml) at 1 hr after an intravenous dose of 2 g; after 5 hr the average level in serum was 8.5 micrograms/ml (range, 2-20 micrograms/ml). The mean (+/- SD) level of cefoxitin in myocardial tissues from eight rabbits at 1 hr following a 250-mg/kg dose of the antibiotic was 4 +/- 0.5 micrograms/g. On the average, patients were treated for 29 days (range, 14-40 days), and they became afebrile in 6.2 days (range, three to 20 days). Both clinical and microbiologic responses to cefoxitin therapy were excellent in 10 patients with monobacterial infections. Both patients with polymicrobial infections were not cured. One, who was infected with a mixed flora of anaerobes, died; the other was cured after surgical valvectomy. These results suggest that cefoxitin is effective in the treatment of endocarditis due to a single susceptible organism but that this antibiotic should be used with caution in patients whose endocarditis is caused by a mixed population of bacterial pathogens.